INVITED REVIEWCell death induced by acute renal injury: a perspective on thecont - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:35 |只看该作者 |倒序浏览 |打印

作者：Babu J.Padanilam作者单位：Department of Physiology and Biophysics, University ofNebraska Medical Center, Omaha, Nebraska 68198-4575

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      【摘要】
   In humans and experimental models ofrenal ischemia, tubular cells in various nephron segmentsundergo necrotic and/or apoptotic cell death. Various factors,including nucleotide depletion, electrolyte imbalance, reactive oxygenspecies, endonucleases, disruption of mitochondrial integrity, andactivation of various components of the apoptotic machinery, havebeen implicated in renal cell vulnerability. Several approaches tolimit the injury and augment the regeneration process, includingnucleotide repletion, administration of growth factors, reactive oxygenspecies scavengers, and inhibition of inducers and executioners of celldeath, proved to be effective in animal models. Nevertheless, aneffective approach to limit or prevent ischemic renal injury inhumans remains elusive, primarily because of an incompleteunderstanding of the mechanisms of cellular injury. Elucidation of celldeath pathways in animal models in the setting of renal injury andextrapolation of the findings to humans will aid in the design ofpotential therapeutic strategies. This review evaluates ourunderstanding of the molecular signaling events in apoptotic andnecrotic cell death and the contribution of various molecularcomponents of these pathways to renal injury. ! i$ Z, [5 s7 ~) S8 F. {
      【关键词】 renal ischemia molecular components signal transduction renaltubular epithelial cells therapeutic approaches
   INTRODUCTION* D8 t4 m% |2 r  A' k2 q. Z0 X
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CELLULAR DEATH AND RESORPTION arecritical biological processes that are crucial not only to normalhistogenesis and organelle turnover but also to the pathogenesis oftissue injury and diseases ( 67, 73, 99, 141, 188, 199 ).Normal physiological cell death or programmed cell death (PCD) occurscontinuously in proliferating tissues and counterbalances excessivecell proliferation during mitosis. PCD is an integral part ofmaintaining the normal functioning of the immune system and insculpting the early embryo ( 67, 188, 199 ). Nonsynchronizedapoptosis can result in pathophysiological outcome and isimplicated in causing a variety of human diseases. Excessive PCD canlead to impaired growth and development, neurodegenerative diseases,and acquired immunodeficiency syndrome ( 14, 193 ). On theother hand, indiscrete suppression of apoptosis can result inautoimmune diseases and cancer ( 62, 101 ). Tissue injury resulting from hypoxic-ischemic, toxic, and thermal insults can result in both pathological cell death (necrosis) and PCD(apoptosis). Unlike apoptosis that occurs in normal anddisease states, necrosis is induced only when cells or tissues areexposed to severe and acute injury ( 60, 97, 149 ). Themolecular pathways leading to the different modes of cell death invarious human diseases and clinical conditions and their regulationhave been under intense scrutiny during the past two decades.Dissecting and discriminating the roles of key molecules in variouscell death programs are crucial as they are attractive targets fortherapeutic intervention.4 P# _, T7 ?; Q( T! c

MODES OF CELL DEATH

A distinction between the morphology of cells undergoingphysiological cell death and pathological cell death was observed morethan 50 years ago ( 67 ). However, it was not until theseminal report by Kerr et al. ( 101 ) in 1972 thatcytologists and pathologists adopted the term "apoptosis"for a morphologically distinct form of cell death. The perpetual flowof information in the past two decades defining the effector andregulatory pathways that result in apoptosis has raised furtherinterest in the role of this mode of cell death in various diseases andpathological conditions, including ischemia-reperfusion injury(IRI) of the heart, brain, and the kidney.( ^) ?9 m# U5 q4 z# u; }
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Apoptosis is highly coordinated and is generally thought to bemediated by active intrinsic mechanisms, although extrinsic factors can contribute ( 16, 30, 205 ). Apoptosis isgenetically controlled and is defined by cytoplasmic and nuclearshrinkage, chromatin margination and fragmentation, and breakdown ofthe cell into multiple spherical bodies that retain membrane integrity ( 25, 101, 138, 246 ). The factors contributing to necrosis are mostly extrinsic in nature, such as osmotic, thermal, toxic, hypoxic-ischemic, and traumatic insults ( 25, 60 ).Necrosis is characterized by progressive loss of cytoplasmic membraneintegrity, rapid influx of Na  , Ca 2 , andwater, resulting in cytoplasmic swelling and nuclear pyknosis ( 9, 18, 200, 244 ). The latter feature leads to cellular fragmentation and release of lysosomal and granular contents into thesurrounding extracellular space, with subsequent inflammation ( 138 ). A recent report indicates that the release of thehigh-mobility group 1 protein by necrotic cells is involved inpromoting the inflammation. Cells deficient for high-mobility group 1 protein showed greatly reduced ability to promote inflammation( 201 ).
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Apoptosis and necrosis often occur simultaneously in a widevariety of pathological conditions as well as in cultured cells exposedto physiological activators, physical trauma, or toxins and chemicals( 141 ). The same type of insult can induce either apoptosis or necrosis, but whether one mode of cell death ispreferred over the other usually depends on the severity of the insultand the idiosyncrasy of the target cell ( 9, 25, 128, 141 ). The perception that apoptosis and necrosis are functionallyopposed forms of cell death is fading, and a consensus has developedthat both forms of cell death constitute two extremes of a continuum.
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MORPHOLOGICAL, BIOCHEMICAL, AND MOLECULAR MARKERS OFAPOPTOSIS AND NECROSIS
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In settings of acute injury such as IRI to the kidney whereapoptosis and necrosis coexist ( 204, 205 ),discriminating between the two modes of cell death is essential.Despite the recent progress in elucidating the molecular determinantsof cell death, a precise histological or biochemical marker todifferentiate apoptosis from necrosis has not been identified.Detection of structural alterations using electron microscopy asdescribed originally by Kerr et. al ( 101 ) still remains asthe reliable criterion to distinguish between the two modes of celldeath. It is now agreed upon that a rational combination of atleast two techniques should be utilized, one to visualize morphologicalchanges and the second to determine biochemical changes, when the twomodes of cell death are asserted.4 P7 ]  s8 l, Q) y( y
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MORPHOLOGY OF APOPTOSIS# P# t, j: k7 y
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In apoptosis, the earliest characteristic change occurs inthe nucleus with chromatin condensation, pyknosis, and karyorrhexis ( 101, 246 ). The condensed chromatin appears as crescentsalong the periphery of the nuclear membrane or as spherical bodieswithin the nucleus. The cytoplasmic condensation instigates the cell toshrink and form numerous vacuoles within the cytoplasm ( 99, 246 ). Subsequently, the nuclear and plasma membranes becomeconvoluted, and small masses of condensed chromatin undergofragmentation along with condensed cytoplasm to form "apoptoticbodies." Apoptotic bodies are plasma membrane bound and oftencontain functional mitochondria and other organelles( 246 ). The stereotypical morphological changes associatedwith apoptotic cell death are depicted in Fig. 1. The phosphatidyl serine residues thatare normally localized to the inner membrane are relocated to theoutside of the cell membrane before its fragmentation. The phosphatidylserine residues on the apoptotic bodies serve as a signal to theneighboring healthy cells to phagocytose and clear the cellular debris,thus avoiding an inflammatory response ( 211 ). In a recentreport, Brown et. al ( 24 ) provide evidence that homophilicbinding between the adhesion receptor CD31 (platelet-endothelial celladhesion molecule-1) present on leukocytes and macrophages plays a keyrole in phagocytosis. Both viable cells and dying cells attach tomacrophages through these receptors, but the viable cells get detachedthrough an unknown repulsive mechanism. The repulsive signaling isimpaired in the dying cells, and they are engulfed ( 24 ).It is not known at present whether analogous systems exist in cellsother than leukocytes. In vitro, in the absence of phagocytosis,apoptotic bodies ultimately will swell and lyse, and this terminalprocess of cell death has been termed "secondary necrosis."Secondary necrosis may occur in vivo in autoimmune disorders associated with impaired clearance of apoptotic cells ( 243 ).
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Fig. 1. Illustration of the variousstages of apoptotic cell death. A : depiction of thestereotypical changes including condensation, changes in nuclearstructure, and fragmentation of the cell into small apoptoticbodies. In vivo, the apoptotic bodies are phagocytosed byneighboring cells, whereas in vitro they undergo swelling and eventuallysis (secondary necrosis). B : photographs ofLLC-PK 1 cells undergoing apoptosis at thecorresponding stages as shown in A. Apoptosis wasinduced by overnight exposure of the cells to 50 µM cisplatin. Thecells in the first 3 photographs were stained with Hoechst dye, and thecells in the last photograph were stained with acrydine orange andethidium bromide. In the last photograph, viable cells appear green,whereas the apoptotic cells with intact plasma membrane appeargreen with yellowish dots representing condensed chromatin;apoptotic cells and bodies that are undergoing secondary necrosisappear bright orange or red due to the plasma membrane damage and entryof ethidium bromide.
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MORPHOLOGY OF NECROSIS; M8 K* \7 W4 S( x. s4 k

The morphology of a necrotic cell is very distinct from that of acell undergoing classic apoptosis, with ultrastructural changesoccurring in both the cytoplasm and the nucleus. The main characteristic features are chromatin flocculation, swelling and degeneration of the entire cytoplasm and the mitochondrial matrix, blebbing of the plasma membrane, and eventual shedding of the cytoplasmic contents into the extracellular space ( 100 ).Unlike in apoptosis, the chromatin is not packed into discretemembrane-bound particles, but it forms many unevenly textured andirregularly shaped clumps, a feature that is being used fordifferentiating between the two modes of cell death ( 224 ).The mitochondria undergo inner membrane swelling, cristeolysis, anddisintegration ( 112 ). Polyribosomes are dissociated anddispersed throughout the cytoplasm, giving the cytoplasmic matrix adense and granular appearance. Dilation and fragmentation of thecisterns of rough endoplasmic reticulum and Golgi apparatus arefrequently observed ( 225 ).
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ENDONUCLEASES AND DNA FRAGMENTATION IN APOPTOSIS ANDNECROSIS

Analysis of DNA fragmentation by agarose gel electrophoresis isone of the most widely used biochemical markers for cell death. Thedetection of internucleosomal DNA cleavage (DNA laddering) isconsidered to be an indicator of apoptosis, whereas the random digestion of DNA resulting in a smear pattern is a marker of necrotic cell death ( 4, 8, 245 ). However, recent data from several studies indicate that discriminating between apoptosis andnecrosis based on DNA fragmentation pattern is questionable, becauseboth modes of cell death can occur in the absence or presence of DNA fragmentation ( 49, 192, 229 ).) G6 d% a7 b9 X1 g; n$ V6 N8 `8 m

The cleavage of double-strand DNA in apoptotic DNA degradation isbelieved to occur by the activation of endogenousCa 2  /Mg 2  -dependent endonucleases thatspecifically cleave between nucleosomes to produce DNA fragments thatare multiples of ~180 base pairs ( 35, 229 ). DNAfragmentation represents a point of no return from the path to celldeath, because no more new cellular protein synthesis for cell survivalcan occur. Although several endonucleases that are involved inapoptosis have been identified and characterized in the pastseveral years, the indispensability of these enzymes for theapoptotic process has been lacking. Two newly identified apoptotic endonucleases [caspase-activated DNAse (CAD) andendonuclease G (Endo G)] with different enzymatic properties appear tobe involved in cellular disassembly and cell-autonomousapoptosis ( 123, 131, 180 ). The biochemicalpathways and the candidate endonucleases involved in DNA degradationare shown in Fig. 2.
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Fig. 2. Pathways leading to DNA degradation. Mitochondrialderived endonuclease G (Endo G) and nuclear-derived, caspase-activatedDNAse (CAD) are 2 known apoptotic endonucleases involved in nuclearDNA degradation. After an apoptotic stimulus, caspase-3 cleaves theinhibitor of CAD (ICAD)/CAD complex and activates CAD to elicit DNAfragmentation in dying cells. Endo G is released from mitochondria inresponse to various apoptotic stimuli and translocates to nucleus,where it is involved in DNA degradation. The apoptosis-inducingfactor (AIF) derived from mitochondria is not a self-nuclease but mayparticipate in DNA degradation, possibly by recruiting otherendonucleases. Unlike CAD, activation of Endo G and AIF is independentof caspase activation. It is possible that Endo G and AIF mayparticipate in nuclear DNA degradation when caspase activation islimited.3 c7 C( ]- i$ y! Q9 O+ S
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CAD is a magnesium-dependent endonuclease that normally resides inthe nuclei bound to its chaperone and inhibitor of CAD (ICAD). On anapoptotic stimulus, caspases-3 or -7 or granzyme B cleave ICAD,dissociating it from CAD, which results in activation of CAD andapoptotic internucleosomal DNA degradation ( 57, 198, 256 ). ICAD is essential for proper folding of CAD and itsactivation ( 161 ). Targeted deletion of ICAD led to absentapoptotic DNA cleavage in thymocytes and splenocytes treated withstaurosporine ( 254 ). However, DNA fragmentation did occurin certain tissues from ICAD-deficient mice, suggesting thatendonucleases other than CAD may also participate in the apoptotic process.8 Y2 i# [: w5 V5 [3 y
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Endo G

A search for the endonucleases that are responsible forCAD-independent DNA fragmentation using biochemical and genetic methods identified mitochondrial Endo G as a second apoptotic endonuclease. Endo G is released from the mitochondrial intermembrane space andtranslocates to the nucleus to elicit DNA fragmentation ( 123, 180 ). Endo G activity is stimulated by DNA breaks, and itsspecificity for DNA degradation is more toward single-strand DNA thanduplex DNA. Thus, unlike CAD, Endo G is a mitochondria-derivedendonuclease whose activity is independent of caspase activation.4 u7 \' M  b- q( M

Apoptosis-inducing factor (AIF) is another molecule involved inchromatin degradation independent of caspase activation. AIF, on itsrelease from mitochondrial intermembrane space, migrates to thenucleus, interacts with DNA ( 248 ), and induces partial chromatin condensation and large-fragment (50-kb) DNA fragmentation. However, AIF has no intrinsic endonuclease activity, and AIF-mediated DNA degradation does not require caspase activation ( 93, 216 ). It is yet to be determined whether Endo G, CAD, or otherendonucleases participate in AIF-mediated DNA degradation( 255 ).8 a) K- e9 K, x: X  O# S' F

MOLECULAR MECHANISMS OF APOPTOSIS# q, @1 W$ x9 L( [
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Studies by Horvitz and colleagues ( 85 ) firstelucidated the existence of a genetically controlled cell death programin which at least three gene products, CED-3, CED-4, and CED-9,participate to cause selective PCD during Caernohabditiselegans development. Subsequent studies in other organismsrevealed that several cysteine proteases that share homology to CED-3are present in mammalian cells. Fourteen such cysteine proteases havebeen identified so far, and they are identified as caspase-1 tocaspase-14 ( 220, 221 ).
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Molecular Executioners of Apoptosis8 c( I  g& e+ G8 v; Q' i
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Caspases are the molecular executioners of apoptosisbecause they bring about most of the morphological and biochemicalcharacteristics of apoptotic cell death. They are a family ofconstitutively expressed proenzymes that undergo proteolytic processingto generate its activated form ( 212, 220, 221 ).Functionally, the caspase family can be divided into two majorsubfamilies. Caspases-1,- 4, and -5 are involved in the maturation ofcytokines such as interleukin-1 and interleukin-18 and promoteproinflammatory functions. The other members of the family function aspart of the apoptotic pathway, and they are subdivided intoinitiator (caspases-2, -8, -9, and -10) and effector caspases(caspases-3, -6, and -7) ( 212, 220 ). The initiatorcaspases are activated by adapter-facilitated self-cleavage in responseto apoptotic stimuli. The effector caspases are activated throughcleavage by initiator caspases ( 78 ). During apoptosis, the effector caspases cleave numerous proteinslocated in the cell membrane, nucleus, and cytoplasm, and thesignificance of this proteolysis in the apoptotic process isincompletely elucidated. The activation of CAD (see above) tofacilitate DNA degradation ( 57 ), cleavage of nuclearlamins to facilitate nuclear shrinkage and budding ( 189 ),and activation of p21-activated kinase 2 to cause active blebbing inapoptotic cells ( 195 ) are a few of the importantfunctions mediated by caspases in the apoptotic process.
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Mechanisms of Caspase Activation; }; R4 k; X: c2 \% L" ]2 K9 K; q

Two converging molecular signaling pathways can lead to theactivation of caspases, and the choice between the pathways that thecell adapts for its final demise is profoundly influenced by theinitial apoptotic stimulus. The first is the receptor-mediated death-signaling pathway that is triggered mostly by extrinsic signalsexemplified by the binding of a TNF ligand to its receptor (e.g., Fasto the Fas receptor). The second apoptotic pathway ismediated by mitochondria and is triggered mostly by intrinsic stresssignals and developmental instructions ( 82, 92, 94, 252 ).An overview of the two death-signaling pathways is presented in Fig. 3.0 j5 j' A& @8 k8 t7 [, ], M

Fig. 3. Overview of death-signaling pathways in mammalian cells:The death receptor pathway ( left ) is initiated by thebinding of a ligand (Eg: FasL) to its receptor Fas, which results inthe sequential recruitment of FADD and pro-caspase-8. c-FLIP can blockthe recruitment of pro-caspase-8 to the complex. The proximity ofseveral pro-caspase-8 molecules results in its activation. Caspase-8can proteolytically activate caspase-3, or it can cleave Bid to itstruncated form t-Bid, which binds to Bax and gets integrated into themitochondrial membrane to release cytochrome c. In responseto various cellular stress-induced apoptotic stimuli, the intrinsicmitochondrial pathway is activated. This pathway involves thetranslocation of proapoptotic molecules such as Bax from thecytosol to the mitochondrial membrane. Bax can release cytochrome c from the mitochondria into the cytosol. Cytochrome c associates with Apaf-1 and caspase-9 to form theapoptosome and subsequent activation of caspase-3. Mitochondria alsorelease AIF and Endo G, which may exert their effects on the nuclei.Mitochondria released Smac/Diablo and Omi/HtrA2 sequesters inhibitorsof apoptosis (IAPs) to prevent them from inhibiting caspase-3.BNIP3 is a Bcl2 family member that is translocated and integrated intothe mitochondria. Unlike other Bcl2 family members, BNIP3 can inducenecrotic cell death in response to death stimuli. Activation of poly(ADP-ribose) polymerase (PARP) leads to NAD depletion andmay induce mitochondrial depolarization to release AIF. ROS, reactiveoxygen species.

Signaling Through Death Receptors( V5 K0 D& P8 M) h) d6 w# t
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Caspase activation through cell death receptors is mediated by asubset of the TNF receptor superfamily, which includes Fas/CD95, TNFreceptor (TNFR)-1, and death receptor-3. Binding of the ligand trimerizes the receptors and recruits death domain-containing moleculessuch as FADD/MORT, TRADD, and RAIDD to their cytoplasmic regions of thereceptors to form a death-inducing signaling complex ( 92, 94, 238 ). The interactions between death effector domains (DED)present in both FADD and pro-caspase-8 lead to the recruitment ofseveral pro-caspase-8 molecules to the complex. The key initiator caspase that instigates the downstream caspase cascade in the deathreceptor pathway is caspase-8 ( 6 ). The molecular mechanism that mediates the initiator caspase activation is still unclear, but itis thought to be regulated by protein-protein interactions. It issuggested that the close proximity of these molecules will activate thelow intrinsic protease activity in them ( 159 ).Pro-caspase-8 undergoes autoproteolytic activation and initiates acaspase cascade to activate the effector caspases.  R2 }  Y* |4 r+ t0 b# s

c-FLIP is a naturally occurring dominant negative antagonist of deathreceptor-mediated caspase-8 activation and contains two DEDs and adefective caspase-like domain. c-FLIP can associate with DEDs of FADDand caspase-8, thus interfering with the recruitment of caspase-8 toFADD ( 88, 226 ). Mouse embryonic fibroblasts derived fromcaspase-8-deficient mice are resistant to Fas, TNF-R1, or DR3stimulation but susceptible to agents that utilize the mitochondrialdeath pathway ( 232 ). This further demonstrates the crucialrole played by caspase-8 in transducing signals downstream of the death receptors.& F  C. l' b7 s4 s, Y

Mitochondria and Bcl2 Family as Regulators of Cell Death. n. h" {* f, ^  W( _
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The apoptotic signal transduction pathways that are undertakenby the cell in response to an intrinsic signal such as DNA damage,glucocorticoids, perturbations in redox balance, and ceramide andgrowth factor deprivation involve mitochondrial release of proapoptotic molecules ( 92, 108, 215 ). Bcl2 familymembers control the permeability of the mitochondrial outer membrane to release various proapoptotic proteins ( 92 ).
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The ever-growing mammalian Bcl-2 family of apoptotic regulatorsshares homology with the C. elegans antiapoptoticmolecule CED-9 ( 32, 106 ). Based on their structure andfunctional similarities, Bcl2 family members are divided into theproapoptotic (Bax, Bak, and Bok) and antiapoptotic (Bcl2,BclX L, Bcl-w, Mcl-1, and A1) groups ( 92 ). Athird class of death effector molecules sharing homology only to theBcl-2 homology-3 (BH3) domain can activate proapoptotic Bcl2 familymembers or inactivate antiapoptotic members ( 86, 213 ).The family of BH3-only proteins include Bin, Bid, Bad, Bik, BNIP3,Noxa, Puma, and Hrk ( 86, 162, 213 ). Pro- andantiapoptotic members of the Bcl-2 family can homodimerize orheterodimerize, thus forming a large number of combinations within acell. Heterodimerization between a proapoptotic member and anantiapoptotic member can nullify the functions of each ( 191 ). The outcome of a cell that received anapoptotic stimulus is thought to depend partly on the ratio of thedeath promoter to the death suppressor ( 1, 2 ). The precisemechanisms by which the Bcl-2 family members modulate apoptosisare still not completely elucidated, but their key functions revolvearound the release of proapoptotic factors, especially cytochrome c from the mitochondrial intermembrane compartment into thecytosol ( 168, 217 ).
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Several models have been proposed to explain how Bcl-2 family memberscan cause the exit of large molecules such as cytochrome c from the mitochondria. It is suggested that 1 ) Bcl-2proteins may insert themselves into the outer mitochondrial membrane,where they could form channels that allow the passage of molecules( 191 ); 2 ) Bcl-2 family members may interactwith other mitochondrial membrane proteins (e.g., the voltage-dependention channel or VDAC) to form large-pore channels ( 191, 209, 227, 228 ); and 3 ) Bcl-2 family members may altermitochondrial membrane permeability, causing mitochondrial swelling andeventual rupture of the outer membrane, thus releasing intermembraneproteins into the cytosol ( 82 ). Although evidence tosupport all of the above models is presented by various investigators,further studies are needed to resolve this crucial issue.3 j4 o- V2 n! {% C! i; H$ R. D

The release of cytochrome c by mitochondria is almost auniversal feature found in response to various intracellular stimuli, including DNA damage, glucocorticoids, oxidative injury, and growth factor deprivation, although they may not play a significant role inreceptor-mediated apoptosis ( 3, 109 ). Cytosoliccytochrome c triggers the formation of the mitochondrialapoptosome, which consists of cytochrome c, apaf-1, andcaspase-9 ( 92, 94 ). Cytochrome c binds andoligomerizes the adapter protein apaf-1, which recruits pro-caspase-9.This causes pro-caspase-9 to autocatalytically activate to form itsactive form caspase-9 and proteolytically activate caspase-3. Asexpected, cytochrome c -deficient embryonic stem cells wereresistant to UV light and staurosporine-induced apoptosis andpartially resistant to apoptotic stimuli from serum deprivation.However, cytochrome c -deficient cells readily underwent apoptosis in response to receptor-mediated apoptoticstimuli ( 92, 94 ).% k( N; J- d  U& m

In addition to cytochrome c, mitochondria release a largenumber of other polypeptides, including AIF ( 135 ), Endo G(see above), second mitochondrial activator of caspases (Smac/DIABLO) ( 52 ), HtrA2/Omi ( 124 ), and pro-caspases-2,-3, and -9 from the intermembrane space ( 134 ). Smac/DIABLOand HtrA2/Omi promote apoptotic cell death by inhibiting a set ofproteins termed inhibitors of apoptosis (IAPs) ( 52, 124 ). IAPs (e.g., c-IAP1, c-IAP2, X-linked IAP, Survivin) canbind to caspases and block cell death induced by a variety of stimuli( 207 ).- d; h  ]: m$ \- ?8 s  [) \& H; W
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AIF is a flavoprotein that translocates from mitochondria to nuclei onapoptotic stimulation and induces caspase-independent chromatincondensation and large-size (50-kb) DNA fragmentation ( 216 ). AIF can also induce mitochondrial release ofcytochrome c and thus augment the cell death process throughthe apoptosome pathway ( 216 ). Recent studies indicate thatheat shock protein 70, which is upregulated in cellular stress( 231 ), exerts its cytoprotective function by binding andinhibiting AIF activity ( 190 ).9 M! f$ E) X3 B

Thus mitochondria participate in the apoptotic pathways through atleast two independent and redundant pathways, one involving theactivation of caspases and the other mediated by AIF. Studies utilizingknockout mice for cytochrome c, apaf-1, caspase-9, and AIFtogether with caspase inhibition studies suggested that AIF-mediated apoptosis is dependent on the initial stimulus( 92 ). AIF-deficient embryonic stem cells, when cotreatedwith caspase inhibitors, were protected from apoptosis inducedby the oxidative stress inducer menadione, whereas it was onlypartially protected from apoptosis in response to serumwithdrawal. The hierarchical nature and the interactions between AIFand the apoptosome in cell death pathways remain largely unknown( 92 ).
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Although the extrinsic and intrinsic signals are considered to take twodistinct pathways to execute cell death, receptor-initiated cell deathcan involve the mitochondrial pathway through the BH3-only protein Bid.In hepatocytes, activation of caspase-8 by Fas leads to cleavage of Bidto its active form t-Bid. t-Bid translocates to mitochondria andassociates with Bcl-2-like proteins to disrupt mitochondrial integrity( 70, 240 ). It should be noted that the cross talk betweenthe two pathways is minimal under most conditions. A recent reportindicates that cytotoxic stress induced mitochondrial permeability, andrelease of various apoptogenic factors is mediated by caspase-2 inhuman fibroblasts transfected with adenoviral oncogene E1A. Smallinterfering RNA (SiRNA)-mediated silencing of caspase-2 expressionprevented cisplatin, etoposide, and UV light-induced apoptosisin these cells. It is argued that in this setting, mitochondria areamplifiers of caspase activity rather than initiators of caspaseactivation ( 114 ).* F* Z: \# U3 _4 B: ^" O
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Mitochondria can also initiate a necrosis-like PCD independently ofcaspase activation. On stimulation by TNF, mitochondria are shown toproduce reactive oxygen species (ROS) that can induce necrotic celldeath, and ROS scavengers attenuated the injury ( 203, 233 ). An impairment in the cytochrome c or AIFpathway can switch the cell death mode from apoptosis tonecrosis. Inhibition of caspases can also switch apoptosis tonecrosis once mitochondria are induced. Thus mitochondria play acentral role in executing different modes of cell death ( 116, 118, 119 ). In addition to mitochondria, several other cellularorganelles may participate in apoptotic cell death, and the detailsare reviewed elsewhere ( 63 ).3 z1 K! K& ~" B1 m6 J8 b' d5 G; Z

APOPTOSIS-BASED THERAPEUTIC AGENTS
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The participation of an ever-growing number of molecules in theapoptotic machinery offers a plethora of opportunities for apoptosis modulation ( 81 ). Various strategies thatare being developed include the use of antisense oligonucleotides,recombinant proteins, small molecules to disrupt protein-proteininteractions, and caspase inhibitors ( 163, 194 ).

An antisense oligonucleotide (G-3139) that targets the first six codonsof the Bcl-2 open reading frame is shown to downregulate its mRNA.Continuous infusion of G-3139 markedly reduced tumor growth of Merckelcell carcinomas that were xenografted into SCID mice. G-3139 ispresently in clinical trials for malignant melanoma and other forms ofhuman cancers. Antisense strategies are also being attempted tomodulate the expression of Bcl-XL, c-FLIP, and survivin( 163 ).# b+ [* N# U4 U% {

Caspase inhibition using active site mimetic peptide ketones, such asfmk [benzyloxycarbonyl (z)-VAD-fluromethylketone], cmk (z-YVAD-fmk/chloromethylketone), z-DEVD-fmk/cmk, and z-D-cmk, haveprovided valuable information regarding their use as apoptotic inhibitors ( 66 ). Caspase inhibition has shown remarkableefficacy in inhibiting apoptotic cell death in different models ofIRI, including cerebral, cardiac, and kidney ( 33, 43, 58 ).Cell-permeable specific caspase inhibitors are being developed byvarious pharmaceutical companies and will undoubtedly be more viable intreating acute injuries such as IRI, transplantation, and cerebralstroke ( 163 ).4 U6 k: ^9 Z/ k! y# P8 i
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MOLECULAR MECHANISMS OF NECROSIS
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Necrosis is the prominent mode of cell death that occurs invarious neurodegenerative conditions and as a consequence toischemic injury in various organs including the brain andheart. Even though great progress has been made in the last decade inunderstanding the molecular mechanisms of apoptosis, thebiochemical pathways leading to necrotic cell death remain poorlyunderstood ( 141 ). Necrosis is long thought to be a"passive" process occurring as a consequence of acute ATPdepletion. Several ATP-dependent ion channels become ineffective,leading to ion dyshomeostasis, disruption of the actin cytoskeleton,cell swelling, membrane blebbing, and eventual collapse of the cell( 9, 137, 169 ). Recent reports suggest that in addition tothe passive mechanisms, "active" mechanisms may also participate inthe necrotic process.8 y) n2 W3 }5 ~, \
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Na Overloading4 ]# Q6 h9 k) w) s4 h
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In ischemia or hypoxic injury, energy depletion occurs bydefective ATP production combined with the rapid consumption of ATP byion pumps and through hydrolysis and leakage. The necrotic volumeincrease associated with necrotic cell death is initiated by an influxof Na and release of ATP due to membrane leakage( 171 ). The increased Na level in the cytosolactivates Na -K -ATPase, resulting indissipation of ATP. In the beginning stages of the injury, asimultaneous efflux of K maintains ion homeostasis. Severedepletion of ATP leads to failure of the pump-leak balance mechanism,leading to an influx of Na and water that results inswelling and collapse of the cell. Thus the overload of Na concomitant with severe ATP depletion seems to be the major determinant of a necrotic outcome ( 27 ). The mechanism by which therapid influx of Na takes place is still not elucidated. Arole for several of the ion channels such as theNa /K pump, Na /H exchanger, Na /Ca 2  exchanger, andNa -K -2Cl cotransporter has beenreported in various cell lines ( 27, 28, 120 ). However, auniversal role for any of these ion channels in augmenting necroticcell death is yet to be established.
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Ca 2 Accumulation

Cytosolic Ca 2  plays a role in linking ATP depletionand necrosis in some cell types ( 9 ), but several othercell types including hepatocytes and renal tubules can undergo necroticcell death in its absence ( 90 ). The ROS-mediated necroticvolume increase and Na influx are suggested to beinitiated by the binding of the free radicals to ion channels includingnonselective Ca 2  channels ( 10, 83, 84, 105 ).The increased levels of Na activatesNa -K -ATPase and consumes ATP, which furtheractivates nonselective Ca 2  channels, resulting in massivecytosolic Ca 2  accumulation. High levels ofCa 2  can participate in ATP depletion by activatingCa 2  -ATPase and mitochondrial depolarization. The increasedlevels of Ca 2  activate endonucleases to degrade DNA andactivate cellular proteases such as calpain to degrade severalstructural and signaling proteins ( 239 ). The role ofCa 2  in oxidative stress is reviewed in detail by Ermak andDavies ( 59 ).* a. m& h' e3 R; j. O3 z) i" E
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Recently, two novel Ca 2  -permeable cation channelsbelonging to the long transient receptor potential (TRP) channelfamily, LTRPC2 and LTRPC7, are found to be activated by a disruption of the redox (oxidation-reduction) status ( 79, 160, 182 ).LTRPC7 is an intracellular ligand-gated ion channel that can permeate both Ca 2  and Mg 2  and is suppressed by higherMg 2  -ATP concentration. In ischemic conditions, thelevels of ATP-bound Mg 2  fall, which may activate inwardand outward currents through LTRPC7 ( 160 ). LTRPC2 is aNSCC that is permeant to both Na and Ca 2 . Itis activated by binding of ADP-ribose and increased concentration ofarachidonic acid and Ca 2  but suppressed by highNa levels. LTRPC2 is activated by micromolar levels ofH 2 O 2 and agents that produce ROS or reactivenitrogen species, thus representing an intrinsic mechanism thatmediates Ca 2  and Na overload in response tochanges in redox status ( 79, 182 ).  L  r3 V; Y$ I/ e; }

Mild oxidative stress such as that induced by moderate levels ofH 2 O 2 can increase cytoplasmic Ca 2  levels by its release from internal stores such as the endoplasmic reticulum (ER). This process is mediated through protein kinase C andionositol triphosphate (InsP 3 ). A recent study demonstrated that in C. elegans, the Ca 2  -binding proteinscalreticulin and calnexin are essential for stimulating necrosis bystresses not involving Ca 2  influx across the plasmamembrane ( 247 ).
  b. B( {0 ?0 K) f2 J$ O* R0 {  n* h
The Mitochondrial Connection

It is well known that mitochondria participate in necrotic andapoptotic cell death by opening the mitochondrial permeability transition pore. Several second messengers and proapoptoticproteins including Bcl2 family members can induce the permeabilization of the mitochondrial permeability transition pore ( 38, 108 ). BNIP3 is a member of the Bcl2 family that is looselyassociated with mitochondria in the normal state but gets fullyintegrated into the mitochondrial outer membrane after a deathstimulus. BNIP3-transfected cells are found to undergo cell deathindependently of Apaf-1, caspase activation, cytochrome c release, and nuclear translocation of AIF. The cells exhibitedmorphology typical of the necrotic form of cell death with plasmamembrane permeability, mitochondrial damage, extensive cytoplasmicvacuolation, and mitochondrial autophagy. It is proposed that BNIP3 canmediate necrosis-like cell death through mitochondrial permeabilitytransition pore opening and mitochondrial dysfunction( 230 ). The expression of BNIP3 is shown to be induced inseveral cell lines in response to hypoxic injury. Overexpression of thehypoxia-inducible factor-1 also induced the expression of BNIP3,resulting in a necrotic form of cell death ( 71 ).

One of the major factors that determine whether a cell undergoesapoptosis or necrosis is the level of intracellular ATP. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that adds ADP-ribosepolymers to various proteins and to itself when activated by DNA strandbreaks ( 143 ). PARP activation is thought to exacerbate ATPdepletion and induce necrotic cell death ( 72, 184 ).Overactivation of PARP after a cellular injury can result inconsumption of its substrate -NAD  . In an effort toresynthesize NAD  , ATP is massively depleted and the cellsdie from lack of energy ( 72, 184 ). PARP inhibitionprotected cells from necrotic cell death in neuronal ischemia,myocardial ischemia, and renal ischemia ( 113, 133, 140 ). PARP-deficient mice are protected against neuronaland myocardial ischemic injury and diabetic pancreatic damage( 56, 183, 257 ), but they are susceptible to apoptotic cell death elicited by TNF- and Fas in hepatocytes( 117 ) and -irradiation. Fibroblasts from PARP / mice are protected from ATP depletion and necrotic cell death but notfrom apoptotic cell death ( 72 ). A recent study in L929fibrosarcoma cells showed that ligation of CD95 inducesapoptosis, whereas TNF elicits necrosis in the cells. Furtherinvestigation into the mechanism of this discrepancy showed that TNFinduces PARP activation, leading to ATP depletion and necrosis. Incontrast, CD95 ligation cause PARP cleavage, thereby maintaining ATPlevels, and the cells die by apoptosis ( 136 ).

A recent report by Yu et. al ( 249 ), however, indicatesthat NAD depletion and subsequent energy depletion may notbe the cause of cell death after PARP activation. Instead,NAD decrement may act only as a signal for AIFtranslocation from mitochondria to cytosol and to nucleus. AIFinitiates nuclear condensation and subsequent chromatin fragmentation,culminating in cellular demise.
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CELL DEATH IN ISCHEMIC ACUTE RENAL FAILURE8 u$ H, ?9 z3 t6 r+ G( A
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A reduction in the glomerular filtration rate (GFR) is the primarychange in renal function caused by ARF in humans and experimental animal models ( 53 ). Pathophysiological mechanisms involvedin the decline in GFR can be attributed to persistent vasoconstriction due to an imbalance between vasoconstrictive and vasodilatory mediators( 36, 37 ); vascular obstruction caused byendothelial-leukocyte interactions ( 31, 187 );tubuloglomerular feedback in response to increased solute delivery tothe macula densa ( 104, 142 ); tubular obstruction caused bydetachment of tubular epithelial cells from the basement membrane andback-leak of glomerular filtrate as a consequence of disruption of theepithelial cell layer ( 5, 20, 21, 65 ).
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Vascular Dysfunction in Renal Ischemia, E5 B8 Z+ o/ O/ M7 w
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After an ischemic insult, total renal blood flow returnstoward normal, but marked, regional alterations occur. The outer medullary region is marginally oxygenated under normal conditions andhas high energy demands. The blood flow to outer medullary orcorticomedullary junction region remains ~10% of normal during reperfusion ( 234, 235 ). The microvasculature in thisregion becomes congested due to interstitial edema, red blood celltrapping, leukocyte adherence, and extravasation ( 22 ). Itis still unclear whether the medullary vascular congestion or thepreglomerular vasoconstriction is the primary reason for causing theimpaired GFR ( 206 ). The reduced blood flow and hypoxicconditions that occur in renal ischemia lead to deprivation ofvital nutrients and loss of ATP in the vascular cells and in thenephron segments of the outer medullary region. In the vascular smoothmuscle cells and endothelial cells, disorganization of F-actin isobserved. The endothelial cells undergo swelling, leakage, cellactivation, and dysfunction ( 111, 158 ). Injection ofendothelial cells expressing endothelial nitric oxide synthase intorats subjected to renal ischemia resulted in the implantationof these cells in the renal microvasculature and functional protectionof ischemic kidneys ( 23 ). A recent studydemonstrated that permanent damage to peritubular capillaries occurredin rats that underwent renal ischemia and may partly accountfor the pathogenesis of chronic renal failure in this setting( 11 ).: [3 v& n$ v, C

Tubular Dysfunction in Renal Ischemia# x% N+ T0 \) z2 }
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At the tubular level, the S3 segment of the proximal tubule thattraverses the outermedullary segment is extremely susceptible toischemic injury. This is due to their low glycolytic capacity to generate ATP in the setting of rapid ATP depletion resulting fromimpaired oxidative phosphorylation. The acute, severe ATP depletionleads to necrotic cell death. The medullary thick ascending limbs,although situated in the same region, do not undergo the same level ofinjury because they have greater glycolytic capacity to generate ATPunder ischemic conditions ( 20 ). However, the cellsin this nephron segment and other distal tubule cells undergo sublethalchanges and produce various chemokines and cytokines that may haveautocrine and/or paracrine effects on the injury and regenerationprocess of the kidney postischemia ( 125, 127 ). Theavailability of ATP in the distal tubule cells makes them lessvulnerable to injury and to promote apoptotic cell death pathwaysunder severe stress conditions.

Irreversible cell death induced by ischemic, toxic, andobstructive ARF was long considered to be of the necrotic type, but recent data from several laboratories indicate that bothapoptosis and necrosis can occur simultaneously in these formsof ARF in humans and experimental animal models ( 46 ). Therelative contribution of the two mechanisms to the initial cell lossdepends on the severity of the injury and the cell type( 127 ).
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MECHANISMS OF NECROSIS IN RENAL ISCHEMIA

The molecular pathways adopted by the renal tissue that lead tonecrotic cell death after an ischemic episode are not fully understood and are now obscured even more by attempts to explore thecontribution of apoptosis to renal injury. Hypoxia resulting from decreased blood flow leads to a variety of secondary effects, including a breakdown in cellular energy metabolism, endothelial andepithelial cell dysfunction, cell swelling, generation of ROS, increasein free cytosolic Ca 2 , and activation of phospholipases,proteases, and endonucleases ( 20, 197, 229 ). Recentevidence indicates that active mechanisms such as activation of PARPplay important roles in necrotic cell death after renalischemia ( 140 ). A hypothetical scheme ofbiochemical events that may engage in positive-feedback loops toaccelerate cellular disintegration culminating in necrotic cell deathis shown in Fig. 4.' D- a/ N* R' c1 y# b

Fig. 4. Hypothetical sequence of various biochemical eventseliciting necrotic cell death. The acute depletion of ATP associatedwith ischemic-hypoxic injury is exacerbated by mitochondrialdysfunction and activation of various ATP-dependent ion channels, whichfurther depletes ATP by a feedback mechanism. An increase in cytosolicCa 2  and ROS triggers various converging biochemicalpathways, leading to activation of cellular degradative enzymes andultimate cellular disintegration./ p5 R2 u, _- c8 P/ z6 ]9 j0 R
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ATP Depletion% B: T: Z: ?9 E: F: t* S! J. P
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Ischemic and toxic renal injury leads to a rapiddecrease in the level of the adenine nucleotide pool (ATP, ADP, andAMP) ( 241 ). In the absence of reperfusion, the adeninenucleotides are degraded to the purine nucleosides adenosine andinosine and to the purine base hypoxanthine. The purine metabolites andthe base are membrane permeable. Prolonged ischemia will leadto the continued loss of these precursor nucleosides, and the cell is dependent on the endogenous precursor compounds that become available during the reperfusion for ATP resynthesis ( 7, 214 ).Prolonged ischemia also leads to mitochondrial dysfunction andimpaired oxidative phosphorylation. Thus the rate of repletion of ATPis dependent on the severity and duration of the injury ( 125, 129 ).% ?" U; C+ Y0 r3 B- A; P1 {

Na Influx and "Oncosis"
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ATP depletion leads to disruption in the microvillous actin, thecytoskeletal meshwork, and the cortical actin of the proximal tubuleepithelial cell ( 154, 156 ). Disruption of the cortical actin cytoskeleton leads to redistribution ofNa -K -ATPase to the apical membrane of theproximal tubule epithelial cell, and this will alter theNa handling of the proximal tubule ( 155, 157 ). A high fraction of filtered Na will reach themacula densa and result in increased vasoconstriction via thetubuloglomerular feedback mechanism ( 153 ). Prolonged ischemia can compromise Na -K -ATPaseactivity, leading to influx and accumulation of Na  ,Cl, and water in the cytosol. Severe depletion of ATPleads to failure of the pump-leak balance mechanism, resulting in cellswelling or oncosis, a typical feature of necrosis ( 241 ).& E' A- V, J4 y" }8 C  d8 Z
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Increased Cytosolic Ca 2 Concentration3 t* L5 C$ K% ]' Z! `

Renal proximal tubular cells undergo a significant increase infree cytosolic ionized Ca 2  concentration([Ca 2  ] i ) from 170 to 390 nM during a 5-minexposure to hypoxic injury. The increase in Ca 2  precededhypoxic membrane damage and was reversible if reoxygenated beforethe cell undergoes lethal injury ( 53 ). A role forCa 2  in mediating the injury is further substantiated bythe findings that removal of extracellular Ca 2 , andchelation of intracellular Ca 2 , protected the cells fromhypoxic injury ( 53 ). Furthermore, Ca 2  channelblockers are found to ameliorate ischemic renal injury inexperimental animal models and in humans. Overloading ofCa 2  in mitochondria results in uncoupling of oxidativephosphorylation and subsequent reduction in ATP synthesis and increasedproduction of superoxides. The mechanisms by which a rise inCa 2  level contributes to the pathophysiology of ARF mayinclude activation of Ca 2  -dependent proteases,phospholipases, and endonucleases ( 20, 53 ).& B2 `& m/ B7 P7 k- N4 s$ j/ B& @  U$ T

Proteases1 O+ d' h8 d  X, `

Prolonged increases in [Ca 2  ] i levelsactivates the Ca 2  -dependent cysteine protease calpain.Renal proximal tubules constitutively express calpains and areactivated in response to toxic and hypoxic injuries. Inhibition ofcalpain activity using various pharmacological agents amelioratednecrotic cell death in proximal tubule cells (PTC) subjected to hypoxicinjury or ATP depletion ( 80, 130, 202, 208 ).

Meprin (metallopeptidase from renal tissue) is a zinc-dependentmetalloendopeptidase that is present in the brush-border membrane ofrenal proximal tubular epithelial cells, accounting for ~5% of thetotal tubular protein ( 223 ). Meprin is localized to the apical brush border ( 29, 237 ). After renal tubularepithelial cell injury, it translocates to the basement membrane andcleaves one of the basement membrane components, nidogen. Mouse strains expressing lower levels of meprin are less susceptible toischemic injury compared with those expressing normal levels( 223 ). Exogenously added meprin is cytotoxic to renal PTC,and inhibition of meprin provided both histological and functionalrenal protection after ischemic injury ( 29, 237 ).: q( C- R8 p4 n2 I
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Phospholipases! H% V& ^) _% z3 b! R

Ischemic cell injury is associated with phospholipolysisand activation of various phospholipases. PLA 2 is one ofthe acyl hydrolases with various isoforms that are dependent on orindependent of Ca 2  for their activation ( 19 ).PLA 2 activation causes membrane phospholipid breakdownduring ischemic injury in various tissues including the kidney( 185, 186 ). The mechanism by which PLA 2 activation appends the injury is not clear. It is possible that thebreakdown in cell membrane integrity, generation of inflammatory mediators, and the cytotoxicity resulting from the accumulation oflysophospholipids and free fatty acids accentuate cellular injury( 20, 144 ). The role of free fatty acids in mediating theinjury, however, is controversial because exposure of proximal tubulesto unsaturated free fatty acids protected against hypoxic injury( 250, 251 ).
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Endonucleases0 c& L7 o" O, G( |+ u  r6 \
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Fragmentation of DNA has been demonstrated after IRI in animalmodels and hypoxia/reoxygenation injury in isolated PTC culture models( 15, 49, 89, 204 ). DNA ladder formation and DNA strandbreaks demonstrated in postischemic kidneys and isolated proximal tubular cells were characteristic of endonuclease activation. A 15-kDa nuclear endonuclease and a 30-kDa cytosolic DNAse/endonuclease that are induced and activated postischemic renal injury have been described ( 13 ). Inhibition of the activities of theseendonucleases protected renal cells from hypoxia-mediated necrotic celldeath. The mechanisms by which these enzymes are activated are notelucidated. It is proposed that the DNA strand breaks induced byoxidative damage may induce and activate the endonucleases. IRI leadsto massive DNA damage shortly after injury in renal epithelial cells ( 229 ). The degree of DNA damage that renders cell deathirreversible and whether inhibition of the activity of theendonucleases at the reversible stage ameliorate cell death in renalischemia are not known.
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IRI in the kidney is associated with generation of ROS in theneutrophils and in parenchymal cells such as proximal tubules andendothelium. The various sources of production of ROS include theimpaired mitochondrial electron transport chain, cyclooxygenases, lipoxygenases, and xanthine oxidase ( 219 ). The superoxidescan react with nitric oxide (NO) and form peroxynitrate ( 53, 69 ). ROS has been implicated in mediating ischemic renalinjury, and treatment with antioxidants or free radical scavengersameliorated renal injury ( 23, 167, 181 ). The mechanisms bywhich ROS induce damage to the cells include peroxidation of lipidmembranes, protein denaturation, and DNA strand breaks( 34 ). The massive DNA damage associated with renalischemia leads to excessive activation of the DNA repair enzymePARP ( 64, 140 ) and subsequent ATP depletion ( 72, 253 ).
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PARP+ M+ f7 Q. T# [' A8 t2 c

Inhibition of PARP protected renal PTC from oxidant injury andnecrotic cell death. Prolonged incubation of renal PTC in the presenceof PARP inhibitors, however, induced apoptotic cell death. Themechanism of induction of the apoptotic pathway in the absence ofPARP is yet to be determined. Administration of PARP inhibitors to ratspost-ischemic renal injury prevented the decline of ATP inrenal tissues. The levels of serum creatinine and BUN values returnedto normal levels at a faster rate in PARP-inhibited animals comparedwith that in vehicle-treated animals ( 140 ).

Inducible Nitric Oxide Synthase and Osteopontin

NO produced in the renal proximal tubules in response toischemic injury is mediated by the inducible form of nitricoxide synthase (iNOS) ( 181 ). Mice deficient for iNOS areprotected against ischemic renal injury ( 69 ).Specific inhibition of iNOS using antisense oligonucleotides beforeinducement of ischemic renal injury also resulted in a dramaticfunctional protection of kidneys from acute ischemia in rats( 69 ). There is some evidence that expression of iNOSpost-renal injury may be modulated by osteopontin. Recombinantosteopontin can inhibit iNOS expression and production of NO in renalepithelial cells ( 87 ). Osteopontin and its receptor CD44are highly induced postinjury in distal tubules, and administration ofrenoprotective agents such as IGF-1 further enhanced its expression( 121, 177 ). Osteopontin-deficient mice are moresusceptible to injury and showed increased levels of iNOS expressionand prevalence of nitrosylated proteins ( 166 ).

Protein Kinases
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The PKC family of serine-threonine kinases encompasses 12 different isozymes. PKC can be activated by Ca 2 ,phosphatidyl serines, and diacylglycerol. The PKC family transduces amyriad of signals by activating G protein-coupled receptors, tyrosine kinase receptors, and nonreceptor tyrosine kinases( 164 ). The increased levels of intracellularCa 2  and the phospholipid hydrolysis products that exist inrenal tubular cells postischemia provide a suitable environmentfor PKC activation. PKC isozymes and the receptor for activated C kinase are induced and activated post-ischemic injury invarious tissues including the kidney ( 173, 174 ). PKC-,- II, and - are induced and translocated to subcellular componentspostischemia in rat kidneys ( 173 ). Exposure ofLLC-PK 1 cells to oxidant injury induced expression of PKCisozymes. Activation of PKC is shown to protect the cells from oxidantinjury and subsequent necrotic cell death ( 175 ). Themechanisms by which PKC activation ameliorates necrotic cell death areyet to be addressed. Recent reports indicate a role for PKC inischemic preconditioning and heat shock-induced renalprotection ( 115, 147 ).. E( u, [( I, A, H. J
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SAPK/JNK is a member of the MAPK family. SAPK transduces signals to thenucleus in response to cellular stresses such as inflammatory cytokines, ischemia, reversible ATP depletion, heat shock, and genotoxic stress. SAPK activity is markedly increased in the proximal and distal tubules after IRI ( 110, 178 ). Inhibition ofSAPK activity during ischemia ameliorates renal failure( 48 ). ERKs are another class of the MAPK family involvedin mitogenic response and cellular differentiation. ERK is alsoactivated post-renal injury, but its expression is localized to thickascending limbs in the inner stripe. Studies in several cellularsystems have suggested that JNK activation can be modulated by thecoexpression of ERKs. It is suggested that the activation of the ERKsin distal tubules during ischemic insult may protect the cellsfrom the injurious effects of JNK activation ( 47 ).. F/ s( d$ [) W, A' I1 Y0 m# A+ r5 m. v
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MOLECULAR MECHANISMS OF APOPTOSIS IN RENALISCHEMIA4 H2 t, Z$ B- [$ s' q9 k: s
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Apoptotic cell death has been documented in experimentalanimal models and humans post-renal ischemia, and inhibition ofapoptotic cell death is shown to ameliorate the injury andinflammation ( 42, 43 ). Several factors that can inducenecrotic cell death, including growth factor deprivation, loss ofcell-cell and cell-matrix interactions, cytotoxic stimuli, and celldeath receptor activation, are also suggested to trigger apoptoticcell death in renal ischemia ( 126 ). The severityof the injury caused by these factors and the degree of cellular ATPand/or GTP depletion play crucial roles in determining the mode of celldeath ( 126 ). A severe depletion of ATP favors necroticcell death whereas GTP depletion is shown to promote apoptotic celldeath ( 98, 126 ). The elucidation of various apoptoticpathways and the identification of the vast array of molecules thatregulate apoptosis provide new opportunities for investigatingthe mechanisms by which apoptotic cell death occurs in renal ischemia.- L+ r% m- ^+ }% ~3 t9 {* j0 U7 b

DEPLETION OF GTP

GTP and GTP-binding proteins play major roles in signaltransduction pathways, leading to cell growth, receptor activation, andcellular homeostasis. Selective depletion of intracellular guanylatesresults in inhibition of proliferation and induces apoptosis inpancreatic cells ( 122 ). It is speculated that the celldeath induced by GTP depletion might be modulated or mediated byGTP-binding proteins.

Among the various factors contributing to ischemic injury, ATPdepletion has always been assumed to be the main culprit( 128 ). The role of other cellular nucleotide pools inischemic conditions was not investigated. Recent reportsindicate that depletion of GTP occurs concurrently with depletion ofATP in in vitro and in vivo models of ischemic renal injury( 44 ). Selective depletion of GTP induced apoptosisin renal tubular cells. Supplementation of guanosine to renal tubularcells subjected to chemical anoxia selectively enhanced GTP levelsclose to normal values and significantly reduced apoptotic celldeath ( 44 ). Administration of guanosine before inducementof ischemic renal injury improved renal functions andsignificantly reduced the number of cells undergoing apoptotic celldeath ( 98 ). The novel finding that manipulation of guanine nucleotide levels could modulate apoptotic cell death in renal ischemia offers new avenues for therapeutic intervention.+ b( t6 ?) c% i# k6 i; a" r! \

TNF Receptor Family-Mediated Apoptosis

Members of the TNF family of receptors including CD95 (Fas),TNFR-1, and CD27 have been implicated in the pathogenesis of IRI( 50, 51, 61, 165, 176 ). TNF is a mediator of inflammation, which exerts its biological effects through its interaction with TNFR-1or -2. Induced expression of TNF occurs post-IRI in various organsincluding the kidney. Simulated ischemia in LLC-PK 1 cells induced TNF- mRNA expression and bioactivity. The production of TNF post-renal injury is triggered by the locally produced ROS,which activates the transcription factor NF- B through p38 MAP kinase( 51 ). Inhibition of p38 MAP kinase using specific inhibitors suppressed the expression of interleukin-1 and TNF- and reduced apoptotic cell death in mice and dogs that underwent ischemic renal injury. Neutralization of TNF- bioactivityusing antibodies to TNF- or inhibition of p38-MAP kinase( 146 ) or NF- B activity ( 145 ) preventedapoptosis in LLC-PK 1 cells subjected to simulated ischemia.
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Fas is the best characterized TNF receptor that can triggerapoptosis in various cells including renal tubular epithelial cells ( 103, 172 ). Renal proximal tubular cells subjectedto ATP depletion or exposed to LPS underwent apoptosis and wasaccompanied by increased Fas protein expression ( 91, 102 ).That mice deficient for Fas are protected from ischemic renalinjury suggests an involvement of Fas-FasL system in renalischemia ( 165 ).

Another member of the TNFR family implicated in inducingapoptosis post-ischemic renal injury is CD27. CD27 andits death domain-containing binding partner Siva are induced at sitesof apoptosis in tubular cells post-renal injury( 176 ). Hypoxic injury in LLC-PK 1 cells inducedthe expression of both CD27 and Siva. Transient transfection of Siva inLLC-PK 1 cells induced 100% apoptotic cell death intransfected cells. The role of CD27-mediated cell death post-renalinjury is under investigation.5 x3 X# ^$ g2 p
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Caspases( ^8 }  t% u- ?3 Z! q. F
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Several studies have documented caspase activation after IRI inthe kidney and post-hypoxic injury in renal PTC. The expression ofcaspases-1, -2, -3, -6, -7, -8, and -9 has been characterized in ratkidneys at the mRNA level ( 95 ). The expression andactivity of caspases-1, -2, and -6 are altered in kidneys post-IRI( 96 ). LLC-PK 1 and Madin-Darby canine kidney(MDCK) cells subjected to chemical hypoxia underwent apoptosiswith a marked increase in activation of caspases-3 and -8 ( 55 ). The activation of caspase-3 is accompanied by Baxtranslocation from cytosol to mitochondria and cytochrome c release from mitochondria ( 196, 197 ). Inhibition ofcaspase activity protected the cells from undergoing apoptotic cell death.

Inhibition of caspases using a pancaspase inhibitor is shown to protectkidneys from ischemic injury. The pancaspase inhibitor protectsagainst ischemic ARF in mice by inhibition of apoptosis and subsequent inflammation ( 43 ). The results from thesestudies clearly demonstrate a role for caspases in IRI. However, therole of individual caspases contributing to the injury and inflammation post-renal injury cannot be discriminated from these studies because nonspecific caspase inhibitors were utilized. The availability ofspecific inhibitors of individual caspases will provide better clues asto the functions of individual caspases in renal IRI. Induction of IRIin mice deficient for caspase-1 by two different groups furnishedcontrasting results. Results from one study indicated thatcaspase-deficient mice underwent less severe injury than theirwild-type counterparts and that this was due to impaired interleukin-18activation ( 148 ), whereas a second group found no changesin the severity of the injury between control groups andcaspase-1-deficient mice ( 41 ).
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Mitochondria and Bcl-2 Family Members7 D1 P/ ?( N$ S6 g; i. D# f3 s1 [6 H+ t
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Mitochondria participate in inducing apoptosis after IRIthrough multiple changes, including generation of oxygen free radicals, calcium translocations, altered permeability transitions, and releaseof cytochrome c, apoptogenic factors, and Bcl2 family members. Renal IRI in rats can induce mitochondrial swelling, ruptureof inner and outer membranes, and release of Bcl2 postinjury ( 17 ). A recent study investigated the proximate eventsthat lead to mitochondrial permeability transition and release ofcytochrome c after hypoxia/reoxygenation injury in kidneyproximal tubular cells ( 242 ). A persistent respiratorydefect occurs in complex I-dependent substrates during reoxygenationafter hypoxia, and this defect is associated with condensedmitochondrial configuration and incomplete recovery of mitochondrialmembrane potential. Amelioration of impaired substrate flux throughcomplex I and ATP generation by -ketoglutarate plus greatly improvedmitochondrial function and cellular recovery ( 242 ). Theidentification of these upstream pathways of anaerobic metabolism andthe possibility of metabolic manipulations to improve mitochondrialfunctions at an early stage may help to prevent irreversiblemitochondrial damage in renal ischemia.
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Ischemic renal injury is associated with a marked increase inthe expression of the antiapoptotic Bcl2 family of proteins, Bcl2,Bcl-X L and the apoptotic protein Bax, in distal tubules and moderate increases in the proximal tubules ( 12, 40 ).The marked upregulation of the antiapoptotic proteins in the distal tubules may tip the balance in favor of cell survival, and this imbalance may be involved in its adaptive resistance toischemic injury. It is suggested that this survival mechanismmay allow the cells to produce growth factors that may aid in theprotection and/or regeneration of the distal tubules by an autocrinemechanism and of the more vulnerable proximal tubules by a paracrinemechanism ( 68 )./ ]. e# I4 e# h

The relative expression of the Bcl2 family of proteins in distal andproximal tubules subjected to oxidant injury in vitro is similar tothat seen in in vivo. However, the expression of BclX L isdecreased in PTC and a translocation of BclX L from the cytosol to the mitochondria is observed in the surviving distal tubulecells. No change in the subcellular distribution of Bax was observed inthe surviving distal tubule cells, and it remained widely distributedin the cytosol. The expression of Bcl2 or Bax was also unchanged in PTCpost-oxidant injury. It is unclear if the translocation ofBclX L plays a role in its protection from the oxidativeinjury ( 40 ). In a separate study, proximal tubules subjected to ATP depletion induced by hypoxic injury or impaired oxidative phosphorylation are shown to translocate Bax from the cytosolto the mitochondria. It is suggested that Bax may form pores inthe mitochondrial outer membrane causing the release of cytochrome c from the mitochondrial intermembrane space and mayactivate apoptotic pathways ( 196 ).5 ?3 C" O. @8 M% P! r' j

Growth Factors

Administration of growth factors pre- or postinjury to animalmodels of renal ischemia is shown to ameliorate the injury and enhance renal regeneration. The beneficial effects may be attributed totheir antiapoptotic, proliferative, and proangiogenic influences ( 74-77 ). In addition, they are shown to enhance GFRpostinjury possibly by enhancing NO production, increased local bloodflow ( 39, 54 ), and vasodilatation of renal microvessels injuxtamedullary nephrons ( 222 ).& x- Y9 C; Y8 f% ~: M( m" l  J6 f3 P
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Among the various growth factors, hepatocyte growth factor (HGF) is oneof the most potent renotropic growth factors ( 76, 150, 151, 236 ). After acute renal injury, the expression of the HGFreceptor c-met is exclusively induced in kidneys ( 132 ). HGF, when administered in its peptide form, is rapidly removed fromblood circulation by the liver and has a very short half-life. Recently, it was shown that intravenous administration of a naked plasmid encoding the HGF gene results in its expression for up to 6 days in the kidney ( 45 ). Intravenous administration of asingle dose of HGF plasmid DNA protected tubular epithelial cells fromboth apoptotic and necrotic forms of cell death after folicacid-induced renal injury. This novel gene-delivery system may help tocircumvent the difficulty of maintaining sustainable levels of thegrowth factor in the blood circulation and offers a novel therapeuticstrategy ( 45 ).- f& e2 ~" _5 J  N; `

The Inflammatory Cascade in Renal IRI
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The inflammatory cascade of renal injury is initiated by ATPdepletion and is further exacerbated during reperfusion( 170 ). Several candidate systems that originate fromen4 Z, Y# H% e. m
      【参考文献】
1. Adams, JM,andCory S. The Bcl-2 protein family: arbiters of cell survival. Science 281:1322-1326,1998 .

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2. Adams, JM,andCory S. Life-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci 26:61-66,2001  .; d9 C6 L0 a, e) V- C' m. c
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3. Adrain, C,andMartin SJ. The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. Trends Biochem Sci 26:390-397,2001  .4 n- D( E: V5 r- T6 x8 h* }
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4. Anderson, AJ,Stoltzner S,Lai F,Su J,andNixon RA. Morphological and biochemical assessment of DNA damage and apoptosis in Down syndrome and Alzheimer disease, and effect of postmortem tissue archival on TUNEL. Neurobiol Aging 21:511-524,2000  .
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