Physiology and pathology of endothelin-1 in renal mesangium - 《American Journal of Physiology》美国生理学杂志干细胞之家



免疫细胞治疗专区	欢迎关注干细胞微信公众号

12 3 4 5 6 7 8 9 10 ... 23 下一页

返回列表

查看: 384761\|回复: 228	go Physiology and pathology of endothelin-1 in renal mesangium [复制链接]

轻羽

新手上路

Rank: 1

积分: 0
威望: 0
包包: 0

楼主

发表于 2009-4-21 13:47 |只看该作者 |倒序浏览 |打印

作者：Andrey Sorokin and Donald E. Kohan作者单位：1 Division of Nephrology, Medical College ofWisconsin, Milwaukee, Wisconsin 53226; and Divisionof Nephrology, University of Utah Health Sciences Center and Salt LakeVeterans Affairs Medical Center, Salt Lake City, Utah 84132 - R3 K+ v9 Z" t  M4 s0 N

   # n& B: j% p- J. ^
      " w: S7 ^5 C/ d5 q7 j
                     4 K- N/ _( s, E) M; V" @+ {


         / C- D" R& X; B
         % T$ K( x2 `# l/ ]( u8 k



      / D$ q1 }- X! k2 O4 C0 D4 L
      【摘要】# k5 g/ K$ ?' n. j
   Mesangial cells (MCs) play a central role in the physiology andpathophysiology of endothelin-1 (ET-1) in the kidney. MCs release ET-1 inresponse to a variety of factors, many of which are elevated in glomerularinjury. MCs also express ET receptors, activation of which leads to a complexsignaling cascade with resultant stimulation of MC hypertrophy, proliferation,contraction, and extracellular matrix accumulation. MC ET-1 interacts with other important regulatory factors, including arachidonate metabolites, nitricoxide, and angiotensin II. Excessive stimulation of ET-1 production by, andactivity in, MC is likely of pathogenic importance in glomerular damage in thesetting of diabetes, hypertension, and glomerulonephritis. The recentintroduction of ET antagonists, and possibly ET-converting enzyme inhibitors, into the clinical arena establishes the potential for new therapies for thosediseases characterized by increased MC ET-1 actions. This review will examineour present understanding of how ET-1 is involved in mesangial function inhealth and disease. In addition, we will discuss the status of clinical trialsusing ET antagonists, which have only been conducted in nonrenal disease, as abackground for advocating their use in diseases characterized by excessiveMC-derived ET-1. ; c* ~$ Q* f' M# x7 L% F$ z
      【关键词】 mesangial cell cell signaling receptor pathophysiology0 n# l& O; ]4 K5 ]
   REGULATION OF ENDOTHELIN-1 GENE EXPRESSION IN MESANGIAL CELLS
( C0 Z( r4 m$ M6 |3 `+ \
WHILE THERE ARE THREE MEMBERS of the endothelin (ET) family (ET-1, ET-2, and ET-3), ET-1 is the major renal isoform produced by and actingon the mesangial cell (MC). ET-1 mRNA encodes a 212-amino acid prepropeptidethat is cleaved to 38-amino acid big ET-1, which, in turn, is converted byET-converting enzymes (ECEs) to mature 21-amino acid ET-1( 116 ). There are seven ECEisoforms and three ECE genes: ECE-1a, -1b, -1c, -1d, -2a, -2b, and -3. ECE-1and ECE-2 prefer big ET-1, whereas ECE-3 prefers ET-3( 50 ). The combination of ashort ET-1 mRNA half-life ( 15 min)( 44 ) and limited intracellularstorage of ET-1 results in a close parallel between mRNA levels and peptidesecretion. Thus the release of active ET-1 peptide must be controlled via 1 ) regulation of gene transcription; 2 ) mRNA stabilization;and/or 3 ) regulation of ECE activity.3 q( K7 J1 u0 Y% u# J

Present data primarily implicate transcriptional control of ET-1 synthesis.ET-1 mRNA stability is unchanged by thrombin or cytokines( 25, 65 ), and limited data areavailable on the regulation of ECE expression or activity( 21 ). Numerous stimulimodulate MC ET-1 gene transcription, including vasoactive substances, growthfactors, cytokines, G protein-coupled receptor agonists, and oxygen radicals( Table 1 ). The cooperation of tissue-specific transcription factors conveys a degree of tissue-selective ET-1 mRNA transcription and ensures that ET-1 is not inappropriately activated( 115 ). This cooperation ismade possible by the presence of multiple regulatory elements in the ET-1promoter, including binding sites for activator protein-1, GATA-2,CAAT-binding nuclear factor-1 (NF-1), and cell-specific transcription factors upstream of classic CAAT and TATAA boxes( 93 ). Importantly, theseregulatory elements operate in different cell types, promoting cell-specificregulation of ET-1 mRNA synthesis [e.g., endothelium-specific transcriptionfactors Vezf1/DB1 ( 1 ) and cardiac-specific GATA-4( 72 )].

Table 1. Factors that modulate ET-1 production by mesangial cells
; w' p* m" z7 C! C
Regulation of ET-1 production has been extensively investigated in MCs. The5'-flanking region of the ET-1 gene encompasses positive regulatoryelements (e.g., engaged by thrombin), whereas negative modulation is exertedby the distal 5' portion( 25 ). Upregulation ofprepro-ET-1 expression requires p38 MAPK and PKC( Fig. 1 ). Thrombin andcytokines (TNF and IL-1) synergistically increase ET-1 expression in MCs, aneffect requiring activation of p38 MAPK and PKC, whereas ERK, JNK/SAPK, orintracellular Ca 2 release is uninvolved( 25 ). The events upstream ofp38 MAPK activation likely involve TGF- -activated kinase 1-binding protein-1, TNF receptor-associated factor 2, and several MEKKs ( Fig. 1 ). The ET-1 promoter isalso activated by phorbol myristate acetic acid or ectopic expression ofPKC- 1 in MC ( 32 ).% I! J7 N# ]. H, h; D* y+ w5 B
, C  d* V! J7 [' ^% V: U9 Z
Fig. 1. Proposed signaling pathways regulating endothelin-1 (ET-1) mRNAtranscription in mesangial cells. Upregulation of ET-1 expression requires p38MAPK and PKC. TGF- -activated kinase 1 (TAK1)-binding protein 1 (TAB1) isan essential cofactor required for activation of TAK1 by TGF- andIL-1. TAK1 recruits p38 MAPK via activation of MEK3 and MEK6. MEKK1 canalso be stimulated by TNF in a TNF receptor-associated factor 2(TRAF2)-dependent manner. Little is known about the regulation of MEKK2 andMEKK3. The ability of thrombin to activate MEKK2/3 is hypothetical. PKC isupregulated by diacylglycerol (DG) produced by phospholipase C (PLC) fromphosphatidylinositol biphosphate (PIP 2 ). ASK1, apoptosissignal-regulating kinase 1.

In summary, MC ET-1 release is under complex regulation, with vasoconstrictor, profibrotic, inflammatory, and proliferative agentsaugmenting its release, whereas vasorelaxant agents tend to inhibit itsproduction ( Table 1 ). BecauseMC ET-1 production is essentially regulated at the transcriptional level, changes in its release and subsequent actions are relevant to sustainedbiological effects rather than short-term and rapid modulation of glomerularstructure and function.+ R" R" d  {" r8 T5 g

ET-1 SIGNALING AND ACTIONS IN MCS

ET-1 activates a variety of signaling systems in MCs to effect alterationsin cell contraction, hypertrophy, proliferation, and extracellular matrixaccumulation ( Table 2 ). Theseactions are subsequent to ET-1 binding to its heterotrimeric G protein-coupled receptors, ET receptor A (ETRA) and B (ETRB), both of which are expressed byMCs ( 32, 80, 103, 118 ). ET-1 binds to both receptor subtypes with high affinity ( K d in the 100 pMrange) and typically exerts prolonged effects (up to several hours). Normalplasma levels of ET-1 average 1-2 pM, indicating that the peptideprimarily functions as an autocrine or paracrine factor. This underscores theimportance of viewing MC ET-1 action in the context of the glomerularmicroenvironment.- c. t: v0 s) h- E

Table 2. Stimulatory or inhibitory effects of ET-1 on substances released bymesangial cells

ET-1 receptors couple to members of the Gi, Gq, Gs, andG 12/13 G protein families( 19, 43, 56 ) with resultant modulation of a variety of signaling cascades, including cyclooxygenases, cytochrome P -450, nitric oxide synthases (NOS), the nuclear helix-loop-helixprotein p8 ( 30 ),serine/threonine kinases, and tyrosine kinases( Fig. 2 ). Common to inductionof many of these pathways in MCs, ET-1 activates PLC( 49, 97, 98 ) and PKC( 94 ). Increased inositoltriphosphate levels are associated with cell alkalinization via augmented Na/Hexchange and increased intracellular Ca 2 concentration([Ca 2 ] i )( 3, 94, 96, 97 ). The increase in[Ca 2 ] i is due to release from intracellular stores as well as influx from dihydropyridine-insensitive pathways ( 94 ). Lower ET-1concentrations (0.1-10 pM) cause slow, sustained increases in[Ca 2 ] i that are dependent onCa 2 influx through a voltage channel-independentmechanism, whereas higher ET-1 concentrations ( 100 pM) cause a rapid andtransient increase that depends on Ca 2 release fromintracellular stores via activation of PLC and PKC( 97 ).
" j' }/ i9 X( x2 h4 m
Fig. 2. Schematic representation of ET-1 signaling in mesangial cells. The ET-1receptor is coupled to Gi, Gq, Gs, and G proteins. PKC-,-, -, and - activation stimulates mesangial cell matrixaccumulation. Increased intracellular Ca 2 stimulatesnitric oxide synthase (NOS) production of NO as well as activation ofproline-rich tyrosine kinase 2 (Pyk2)-dependent signaling cascades. NO, viaactivation of PKG, inhibits adenylate cyclase. Pyk2-mediated tyrosinephosphorylation contributes to activation of p38 MAPK and cell contraction.Activation of PKC and the Src family of kinases results in stimulation of theERK-signaling cascade, which controls induction of gene expression, importantfor cell proliferation and hypertrophy. Tyrosine and serine phosphorylation ofadaptor protein Shc isoforms are crucial for the network of ET-1-mediatedsignaling pathways. PI-3-K, phosphoinositol 3-kinase; COX, cyclooxygenase;CaMK II, Ca 2 /calmodulin-dependent protein kinase II;AA, amino acid; PA, phosphatidic acid; IP 3, inositol1,4,5-trisphosphate.( m6 o$ g9 r0 L4 N

Hypertrophy and Proliferation+ n3 ~' M5 @: l. ~1 @' ^6 J5 `

There is abundant evidence that ET-1 directly and indirectly (e.g., viaPDGF) ( 49 ) stimulates MCmitogenesis ( 5, 28, 32, 80, 98 ) as well as partiallymediating the proliferative response to other growth factors (such asangiotensin II) ( 5, 28 ). In fact, ET-1 stimulatesMC proliferation in an autocrine fashion because antisense oligonucleotides toET-1 reduce spontaneous MC proliferation in vitro( 67 ). The mitogenic effects ofET-1 in MCs are likely primarily mediated via ETRA( 28, 105 ), although there are datasuggesting that activation of ETRB, as well as ETRA, in human MCs can induceproliferation ( 32, 80 )( Fig. 3 ).  U; T' N+ f7 ]

Fig. 3. Schematic representation of biological effects mediated by endothelinreceptor A (ETRA) and endothelin receptor B (ETRB) in mesangial cells. The neteffect of ETRA activation is mesangial cell contraction, extracellular matrixaccumulation, and proliferation. The net effect of activation of ETRB tends tobe vasorelaxant as well as causing autostimulation of ET-1 production. AP-1,activator protein-1; MMP-2, matrix metalloproteinase-2.
' ^7 V5 W8 J" u+ b9 y
ET-1 stimulation of MC proliferation involves several pathways, among whichMAPK figures prominently ( 83, 106 ). ET-1 induces activityof all three major MAPK cascades in MCs: ERK1 and ERK2( 112 ), JNK/SAPK( 2 ), and p38 MAPK( 99 ). In addition, ET-1stimulates expression of MAPK phosphatase 1 (MKP-1)( 23 ), a dual-specificityphosphatase that downregulates MAPK signaling. There is convincing evidencethat ET-1 induces cell proliferation primarily via activation of theRas-Raf-Mek-ERK-signaling cascade ( 92 )( Fig. 2 ). Late-onset, stablechanges in gene expression, associated with MC hypertrophy, were recentlyreported to be controlled by ET-1-mediated activation of ERK, JNK/SAPK, and phosphatidylinositol 3-kinase pathways( 30 ). In addition, ET-1 activation of ERK 1/2 is partially dependent on tyrosine phosphorylation ofthe epidermal growth factor receptor and likely involves caveolin-1( 37 ). ET-1 induction of MAPKand subsequent increased cyclin-dependent kinase 4 and cyclin D1 expressionoccur through activation of ETRA( 45, 105 ).

ET-1 rapidly enhances tyrosine phosphorylation of proline-rich tyrosinekinase 2 (Pyk2) and the Src family of cytoplasmic tyrosine kinases.ET-1-induced activation of Pyk2 and Src results in tyrosine phosphorylation ofmultiple signaling molecules, including recruitment of the adaptor proteinsShc and Grb2 that ultimately lead to cell proliferation and/or hypertrophy ( Fig. 2 ). The ubiquitouslyexpressed adaptor protein Shc( 84 ), which exists in threeisoforms with relative molecular masses of 46, 52, and 66 kDa(p46 Shc, p52 Shc, and p66 Shc, respectively), plays an important role in ET-1 signaling. ET-1 treatment of MCs results inpersistent tyrosine phosphorylation of p52 Shc ( 23 ), which promotes theassociation of p52 Shc with the Grb2/Sos complex due to recognitionof p52 Shc P-Tyr by the Grb2 SH2 domain. The formation of thetrimolecular module Shc/Grb2/Sos localizes the guanosine exchange factor Sosto GTPase Ras, causing the switch of RasGDP into the active GTP-bound form. This initial activation of Ras is followed by rapid inactivation of Ras, as adirect consequence of the MEK/ERK-dependent Sos1 phosphorylation and Sos1release from the trimolecular module. Subsequent to Ras and ERK deactivation,Sos1 reverts to the nonphosphorylated condition, enabling it to bind again tothe Grb2/Shc complex, which is stabilized by persistent Shc phosphorylation, resulting in biphasic activation of Ras( 23 ). The second peak of ERKactivation is presumably attenuated by activation of a dual-specificityphosphatase.
7 n7 ^8 x) |: G
ET-1 also induces serine phosphorylation of p66 Shc viaactivation of the MEK/ERK-signaling module, resulting in p66 Shc association with the serine-binding, motif-containing protein14-3-3 ( 24 ).Interestingly, p66 Shc -/- mice are resistant tooxidative stress, and the p66 Shc -mediated response to oxidative stress is dependent on serine phosphorylation( 71 ). So far, ET-1 is amongfew physiological agonists shown to induce serine phosphorylation ofp66 Shc, raising the possibility that ET-1 is involved in cellularresistance to oxidative stress.
% a; \# J: s& c0 @  v; U# n
Cell Contraction

ET-1 potently stimulates MC contraction, an effect that is independent ofdihydropyridine-sensitive Ca 2 channels and is likelymediated through ETRA activation( 3, 91, 102 ). Pyk2 may play a crucial role in ET-1-mediated contraction of MCs because 1 ) it is the onlycytoplasmic tyrosine kinase activated by mobilization of intracellularCa 2 ( 66 ); 2 ) tyrosinephosphorylation appears to be essential for the contractile effects of many Gprotein-coupled receptor ligands( 70, 108, 113, 122 ); 3 ) ET-1stimulates Pyk2 autophosphorylation in a Ca 2 -dependentmanner in MCs ( 99 ); and 4 ) Pyk2 is responsible for p38 MAPK activation in MCs, which has beenimplicated in MC contraction( 99 ). It should be noted thatET-1-mediated contraction also involves activation of the Rhi/Rho kinasepathway because Rhi/Rho kinase inhibition markedly blunts ETRB agonist-inducedvasoconstriction ( 9 ).ET-1-induced MC contraction may also involve Src tyrosine kinases, possiblyvia -arrestin-1-mediated recruitment of Src to a molecular complex withthe endothelin receptor ( 43 )and/or adhesion-dependent activation of Src via interaction with focal adhesion kinase (FAK) ( 10 ).ET-1 may activate Src, at least in part, via activation ofCa 2 /calmodulin-dependent protein kinase II (CaMK II) inMCs ( 111 )( Fig. 2 ).
! Y* N3 j; x/ s- p
ET-1 stimulation of MC contraction may be modified by vasorelaxant substances, particularly nitric oxide (NO) and PGE 2. Activation ofETRB increases cGMP via induction of NO, an effect that is dependent onrelease of Ca 2 from intracellular stores and calmodulin( 81 )( Fig. 3 ). In contrast, ET-1inhibits induction of cytokine-stimulated inducible NOS (iNOS) activity viaactivation of ETRA ( 7, 33 ). ET-1 also stimulatescyclooxygenase (COX) activity, resulting primarily in increases inPGE 2 with small increases in thromboxane A 2 ( 95 ). This occurs via ETRAinduction of PLA 2 ( 26 ) and COX-2( 38 ). COX-2 stimulationdepends on intracellular Ca 2 release, Ca-calmodulinkinases, and nonreceptor-linked protein tyrosine kinase activity( 15 ) and is independent of PKC( 26 ). Recent studies alsodemonstrate that ET-1 enhances nuclear factor of activated T celltranslocation to the nucleus in MCs and increases nuclear factor 2 ofactivated T cell binding to the COX-2 promoter( 101 ).4 w' P( B) c6 [. W* l- ]; R

Extracellular Matrix Accumulation- U* T7 \0 ~) C0 _1 |
/ ]: `2 N5 i) R$ ^
ET-1 increases fibronectin( 28, 82 ), type IV collagen( 28, 114 ), and type I collagen( 82 ) synthesis by MCs( Table 2 ). In addition, ET-1partially mediates angiotensin II-mediated MC extracellular matrixaccumulation ( 28 ). Theseeffects are primarily mediated via ETRA( 28, 55 )( Fig. 3 ) with resultant activation of PKC-, -, -, and - ( 28, 114 ). Induction offibronectin and type I collagen synthesis appears to involve ERK2, but not JNKor p38 MAPK ( 82 ).
: I% k- Q- e( _$ z( e4 S% I* T
ET-1 also seems to have a net inhibitory effect on extracellular matrixdegradation by MCs. Although ET-1 has been described to increase MCcollagenase ( 92 ) and matrixmetalloproteinase-2 activity (MMP-2)( 55 ), the peptide has beenshown to reduce fibrinolytic activity (via stimulation of plasminogenactivator inhibitor production)( 47 ), to reduce basal andcytokine-stimulated MMP-2, and to enhance secretion of tissue inhibitor ofMMP-2 ( 117 ). These lattereffects are also mediated by activation of ETRA( 117 )( Fig. 3 ). Notably, micetransgenic for the ET-1 promoter and gene develop marked glomerulosclerosis in the absence of elevations in systemic blood pressure( 90 ).

PATHOPHYSIOLOGY OF ET-1 IN MCS; O# Y8 P6 y$ x  Y
3 N' I# f  A' A! {
Glomerulonephritis# N" A" x# H% x) M

To demonstrate that MC-derived ET-1 is of pathogenic importance inglomerulonephritis (GN), it is necessary to show that its production isincreased, that this results in a pathophysiological effect, and that blockadeof ET-1 action ameliorates disease severity. As discussed above, inflammatorycytokines increase MC ET-1 release in vitro, suggesting that MC ET-1production should be enhanced in GN. This has indeed been shown in animal models: MC ET-1 production is increased in rat models of immune complex GN( 87 ), nephrotoxic serumnephritis ( 120 ), andmesangial proliferative GN( 119 ). In addition, MC ET-1production is augmented in human systemic lupus erythematosis( 32 ), urinary ET-1 excretionis proportional to the severity of human mesangial proliferative GN( 18 ), and N -formyl-Met-Leu-Phe-stimulated neutrophils from patients with IgAnephropathy stimulate rat MC ET-1 release more than neutrophils from patientswith non-IgA mesangial proliferative GN( 11 ).
0 y# W1 m; \) O* o3 Q8 I, W
As discussed earlier, there is abundant evidence that ET-1 increases MCproliferation and matrix accumulation. ET-1 may further stimulate inflammationbecause it elevates human MC production of TNF, ICAM-1, and VCAM-1( 14 ). Furthermore, ET-1reduces TNF-mediated apoptosis in MCs (via induction of COX-2), potentially causing additional cell accumulation( 46 ). That these effects ofET-1 are of pathophysiological relevance is borne out by studies using ETantagonists ( Table 3 ). Indirectevidence comes from studies in which either an angiotensin-converting enzymeinhibitor (ACEI) ( 87 ) or athromboxane A 2 receptor blocker( 120 ) reduced glomerularinjury in rat models of GN associated with decreased MC ET-1 levels. Moredirect evidence is afforded by several studies. The ECE inhibitor CGS-26303 reduces MC expansion in puromycin aminonucleoside (PAN) nephrosis in rats( 22 ), and an ETRA antagonist,FR-139317, reduces glomerular collagen 1 (IV) and lamininaccumulation in PAN nephrosis( 20 ). In rat models ofmesangial proliferative GN, FR-139317 reduced MC proliferation, combinedETRA/ETRB blockade with bosentan improved renal function and reduced MC ET-1mRNA levels ( 27 ), andantisense oligonucleotides to ET-1 decreased MC proliferation and matrixexpansion ( 67 ). Thus there isstrong evidence that MC-derived ET-1 plays a significant pathogenic role inGN.) A; x  U. q0 c

Table 3. Effects of ET blockers on mesangial cell and glomerular dysfunction inexperimental rat models of renal disease; A7 g0 v* T4 x# ?: ?

Diabetes Mellitus) ?; V. Z& }* Y9 t- G4 X
. \, H# n0 O# e9 _
Although there is no direct evidence in vivo that MC ET-1 production isincreased in diabetic nephropathy, there are in vitro data suggesting that MCET-1 synthesis is increased by hyperglycemia. Furthermore, hyperglycemiamodifies MC responses to ET-1. For example, ET-1-stimulated p38 MAPK andcAMP-responsive element-binding protein phosphorylation in MCs is enhanced byhyperglycemia ( 109 ). Inaddition, hyperglycemia augments ET-1-stimulated 1 (IV)collagen production in MCs, an effect that requires PKC-, -,-, and ERK1/2, as well as PKC- and - (latter independent ofERK1/2) ( 36 ). Interestingly,hyperglycemia decreases the MC ET-1 Ca 2 signal throughdecreased receptor-operated Ca 2 influx( 79 ), an effect that couldexplain hyperglycemic inhibition of ET-1-induced MC contraction( 16 ).

There is abundant evidence in vivo that ET-1 antagonists ameliorate glomerular injury in animal models of diabetic nephropathy ( Table 3 ). ET-1 blockade withcombined ETRA/ETRB inhibition (bosentan) reduced albuminuria and increasedglomerular filtration rate (GFR)( 12 ) and ameliorated mesangialmatrix, fibronectin, and 2 (IV) collagen accumulation indiabetic rats ( 13 ). In addition, combined receptor blockade with LU-224332 for 36 wk preventedfibronectin and collagen IV accumulation in diabetic rats( 35 ). The beneficial effectsof combined blockers may be largely a result of ETRA blockade because 1 ) ETRA blockade with YM-598 reduced albuminuria in a diabetic rats( 100 ); 2 ) ETRAblockade with LU-135252 for 6 mo reduced glomerular histological injury inrats with streptozotocin-induced diabetes( 17 ); and 3 ) ETRAblockade with FR-139317 for 24 wk decreased glomerular mRNA levels ofcollagen, laminin, TGF-, basic FGF, and PDGF-B in diabetic rats( 75 ). Taken together, thesestudies suggest that MC ET-1 production is enhanced in diabetic nephropathy and that excessive ET-1 action in the diabetic glomerulus can cause enhancedmatrix accumulation, proteinuria, and reduced GFR.

Hypertensive Glomerulosclerosis

MC ET-1 production may be elevated in hypertension. MC ET-1 levels arehigher in spontaneously hypertensive (SHR) rats than in nonhypertensivecontrols ( 64 ), whereas MC ETRAmRNA levels are higher in stroke-prone SHR compared with normotensive Wistar-Kyoto (WKY) rats ( 34 ).Several agents also enhance MC ET-1 release more from SHR than WKY animals,including angiotensin II, phorbol ester, vasopressin, thrombin, and PDGF( 41, 42 ). Relevant to these latterfindings is the observation that ACEI reduced ET-1 production by MCs fromuninephrectomized SHR rats ( 64 ). Although data arelimited on the role of MC ET-1 in hypertensive glomerular injury, one studyfound that bosentan reduced glomerular extracellular matrix accumulation in N G -nitro- L -arginine methyl ester-inducedhypertensive mice despite the lack of an effect on blood pressure( 8 ). This study also found thatbosentan normalized the activity of an 1 (I) collagenpromoter-luciferase transgene in these mice. Thus initial studies suggest that MC-derived ET-1 may also play a role in hypertensive glomerulosclerosis.

Acute and Chronic Renal Failure- J, v# f" N2 @& v1 d  _" U

Data on MC ET-1 production or actions in chronic renal failure outside ofthe specific examples above are few, although there is abundant evidence thatET-1 plays a role in the progression of renal insufficiency( 54, 57 ). There is also littleinformation on MC-derived ET-1 in acute renal failure. Numerous studies haveshown that ET-1-induced vasoconstriction is of pathogenic importance invarious forms of acute renal failure( 78 ); however, it is unclearwhether this ET-1 substantially derives from MCs. Agents that induce renalvasoconstriction and/or cause acute renal failure can stimulate MC ET-1release, including cyclosporin, FK506, myoglobin, thromboxane A 2,angiotensin II, vasopressin, and reactive oxygen species( 29, 39, 53, 59, 62, 88, 121 ). It is conceivable thatMC-derived ET-1 in the setting of acute renal failure reduces the glomerular ultrafiltration coefficient by eliciting MC contraction or even contributes todownstream efferent arteriolar vasoconstriction; however, these considerationsare entirely conjectural.
4 n7 ]5 f! N% O% Y2 D0 x
ET ANTAGONISTS IN THE CLINICAL SETTING+ m7 L9 R- e4 n& k# ~% M2 ?$ I
8 {9 O; W2 t- I- i/ F
Given the strong indictment of MC ET-1 overactivity in the pathogenesis ofthe three leading causes of end-stage renal disease, namely, diabetes,hypertension, and glomerulonephritis, there is cause for considerableexcitement about the used of ET-1 blockers in the treatment of these diseases.With the recent Food and Drug Administration approval of an ET antagonist fortreatment of primary pulmonary hypertension, the stage is now set for realistic consideration of the use of this class of agents in treating kidneydisease. To date, there have been no clinical studies that have addressed thisissue; however, studies of other diseases provide an impetus for thetranslation of ET blockers to the therapy for renal disease. This section will review the present status of ET antagonists in the clinical setting, focusingon the cardiopulmonary system. While this material does not cover diseases ofthe kidney, we thought it important at this time to emphasize the work beingdone in other organ systems, hopefully as an impetus for similar studies to beconducted in renal disease.2 `- q6 w" Z8 I4 U2 l

Initial studies focused on the effects of oral combined ETRA/ETRB blockadewith generally disappointing results. One of the earliest studies was a phaseII trial examining the effect of 4 wk of therapy with the combinedETRA/ETRB-receptor antagonist bosentan on blood pressure in 293 patients withmild to moderate essential hypertension( 63 ). Blood pressure decreasedmodestly, and there were a significant number of side effects, including headache, flushing, leg edema, and reversible elevations in liver enzymes(LFTs). Bosentan was then used in a trial of 370 patients with New York HeartAssociation (NYHA) class IIIb/IV congestive heart failure (CHF), the so-calledResearch on ET Antagonism in CHF trial( 74 ). The trial wasdiscontinued prematurely because of elevations in LFTs; however, it appearedthat bosentan initially worsened CHF but may have slightly improved theoutcome after 6 mo. Subsequently, a lower dose of bosentan was administered to1,613 patients with NYHA class IIIb/IV CHF in the ET Antagonist Bosentan forLowering Cardiac Events in Heart Failure trial (ENABLE1 in Europe and ENABLE2in North America) ( 51 ).Unfortunately, no difference was detected between bosentan and placebo on all-cause mortality or hospitalization for CHF. Another trial, the EnrasentanClinical Outcomes Randomized study, using a combined ETRA/ETRB antagonist,found that ET blockade increased heart failure events in 419 patients withNYHA class II/III CHF ( 85 ). Anintravenous ETRA/ETRB blocker, tezosentan, has been given in a trial involving285 patients with acute decompensated CHF (RITZ-2), and there was decreasedpulmonary capillary wedge pressure and increased cardiac output( 68 ). Unfortunately, afollow-up study (RITZ-5) found no affect of tezosentan on the outcome of acutepulmonary edema ( 52 ). Anotherphase II study, using TAK-044, a combined ETRA/ETRB blocker, found no difference in clinical outcomes in patients with aneurysmal subarachnoidhemorrhage ( 89 ). The mostencouraging results using combined ETRA/ETRB blockers have been in pulmonaryhypertension. Bosentan modestly increased exercise capacity in 213 patients; however, 9 patients stopped the drug because of side effects ( 86 ). Finally, there is a casereport of a patient with systemic sclerosis whose digital ulcers and cutaneousfibrosis substantially improved with 1 yr of bosentan therapy( 40 ). In summary, the clinicaltrials with ETRA/ETRB combined blockade in cardiopulmonary disease have eitherbeen unpromising or shown only a modest benefit.

ETRA-specific antagonists could be potentially superior to combined blockers by virtue of avoiding inhibition of NO, or other factor, productionas a result of ETRB blockade. To date, relatively few clinical studies havebeen performed using these agents. Treatment with darusentan (LU-135252) for 6wk reduced mean blood pressure (up to 11 mmHg) in a trial of 392 patients with moderate essential hypertension( 76 ). A 3-wk trial (HEAT) with oral darusentan in 157 patients with NYHA class III CHF showed improvedcardiac index and reduced systemic vascular resistance, with no change in LFTs( 69 ). Treatment withsitaxsentan for 12 wk in 20 patients with NYHA class II-IV pulmonaryhypertension improved exercise capacity( 6 ). Interestingly, a phase II study using ETRA blockade in patients with prostate cancer (prostate cancercell lines express very high levels of ETRA) is underway ( 85 ).- W" X% K- J& B  S. k

Finally, agents are being developed that inhibit ET actions as well asaffect other systems. BMS-248360, a potent inhibitor of ETRA andAT 1 receptors, has recently been described( 73 ). ECE inhibitors have beendesigned, although they have not been clinically tested. Because ECEs share37% sequence homology with neutral endopeptidase (NEP), which degrades atrialnatriuretic peptide and bradykinin, dual ECE and NEP inhibitors have been designed. One such dual inhibitor, CGS-26303, reduces glomerular lesions inrats with PAN nephrosis ( 22 ).Even triple inhibitors (ECE, NEP, and ACE) have been designed: all threeenzymes are zinc metalloproteases and can be inhibited by groups that interact with the zinc-binding domain (e.g., sulfhydryl groups). One such tripleinhibitor, SCH-54470, decreased blood pressure and proteinuria and increasedGFR in the remnant kidney rat model( 110 ). Last, vasopeptidaseinhibitors (inhibiting ACE and NEP) have been designed (e.g., omapatrilat);however, their clinical utility is uncertain( 107 ). Notably, inhibition of NEP can result in elevated ET-1 levels because this metalloprotease degradesET-1.; n( c5 j& O/ W% D. y! ]" e

In summary, the stage is set for clinical trials of ET inhibitors inpatients with glomerular disease characterized by increased ET-1 productionand actions. The challenges include finding an agent with tolerabletherapeutic indexes, targeting ET receptors that most likely are pathogenic(likely ETRA), and, most of all, meeting the challenges of conducting studieswhose benefit may only be truly known after long-term drug administration.

CONCLUSION) o' }# Z6 a5 G: G* K6 X; V
" o4 K8 ^: l0 I: V; M! t9 K
In conclusion, abundant evidence points to a pivotal role for ET-1 in thebiology, and particularly the pathology, of the renal mesangium. The peptideis produced by MCs and can, in turn, act on MCs to elicit proliferation,hypertrophy, contraction, and/or extracellular matrix accumulation. Theseeffects are mediated in large part through activation of ETRA and particularly involve PKC and MAPK. Excessive ET-1 production by, and action on, MCs is ofpathogenic importance in glomerular damage in animal models of GN, diabetes,and hypertension. With the emergence of Food and Drug Administration approvalof clinical ET antagonists, the time is propitious for clinical trials usingET antagonists in these renal diseases. While challenges exist with suchtrials, it is our contention that the preclinical studies are so strongly indicative of a potential beneficial effect of these agents in glomerulardisease that this challenge should be aggressively pursued.
# u( U- R$ _9 f! ]' n* B, R0 E
DISCLOSURES
! p; j. ]* P$ u" g) H
This work was supported by National Institutes of Health Grants DK-59047(D. E. Kohan), HL-22563 (A. Sorokin), and DK-41684 (A. Sorokin).
      【参考文献】
Aitsebaomo J,Kingsley-Kallesen M, Wu Y, Quertermous T, and Patterson C. Vezf1/DB1 is anendothelial cell-specific transcription factor that regulates expression ofthe endothelin-1 promoter. J Biol Chem 276: 39197-39205,2001./ B& j8 o1 c* Y6 q
! h, Y7 {: l! X$ z7 }7 R
, \/ G% y/ v& f# O

Araki S, HanedaM, Togawa M, and Kikkawa R. Endothelin-1 activates c-JunNH 2 -terminal kinase in mesangial cells. KidneyInt 51:631-639, 1997.8 I* X- T* g% P

: L9 w1 b) [, q! x; U0 p4 ]
Badr KF, MurrayJJ, Breyer MD, Takahashi K, Inagami T, and Harris RC. Mesangial cell,glomerular and renal vascular responses to endothelin in the rat kidney.Elucidation of signal transduction pathways. J ClinInvest 83:336-342, 1989.$ Y, r2 G7 }0 w
* P) J7 w+ i6 `2 j

/ T2 B  ^( u+ F/ a3 U& X
Bakris GL,Bhandaru S, Akerstrom V, and Re RN. ACE inhibitor-mediated attenuation ofmesangial cell growth. A role for endothelin. Am JHypertens 7:583-590, 1994.

3 I4 f* \# P: U% ^8 ~/ }# H6 v
Bakris GL andRe RN. Endothelin modulates angiotensin II-induced mitogenesis of humanmesangial cells. Am J Physiol Renal Fluid ElectrolytePhysiol 264:F937-F942, 1993.

, d4 O" x) D9 K6 \  _

Barst RJ, RichS, Widlitz A, Horn EM, McLaughlin V, and McFarlin J. Clinical efficacy ofsitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonaryarterial hypertension: open-label pilot study. Chest 121: 1860-1868,2002., x3 h+ U; ~3 m) w

0 W! m0 ]7 N1 m, ?- L+ Q/ Q0 \! x
, l+ j3 J  M0 k0 A( l+ `
Beck KF,Mohaupt MG, and Sterzel RB. Endothelin-1 inhibits cytokine-stimulatedtranscription of inducible nitric oxide synthase in glomerular mesangialcells. Kidney Int 48:1893-1899, 1995.1 x5 F1 k3 c  h: y: ^# s
) n% q) l6 g9 P
: t- a6 c9 z" ~4 O0 x
" p; \) d0 Z# ^" [+ l' ~
Boffa JJ,Tharaux PL, Dussaule JC, and Chatziantoniou C. Regression of renalvascular fibrosis by endothelin receptor antagonism. Hypertension 37:490-496, 2001.( J! |: j4 S; _4 f& C" L% p

' M( ]! d  f9 l; y

Cavarape A,Endlich N, Assaloni R, Bartoli E, Steinhausen M, Parekh N, and Endlich K. Rho-kinase inhibition blunts renal vasoconstriction induced by distinctsignaling pathways in vivo. J Am Soc Nephrol 14: 37-45,2003.
5 t" R$ S+ w5 o- w8 k+ N

Cazaubon S,Chaverot N, Romero I, Girault J, Adamson P, Strosberg A, and Couraud P. Growth factor activity of endothelin-1 in primary astrocytes mediated byadhesion-dependent and -independent pathways. JNeurosci 17:6203-6212, 1997.

Chen HC, GuhJY, Chang JM, and Lai YH. Differential effects of FMLP-activatedneutrophils from patients with IgA nephropathy enhanced endothelin 1production of glomerular mesangial cells. Nephron 89: 274-279,2001.$ [" l" w  d9 H) v& w

; m; f0 Q8 h( u8 u7 z) S
Chen J, Gu Y,Lin F, Yang H, Zhu W, Ma J, and Lin S. Endothelin receptor antagonistcombined with a calcium channel blocker attenuates renal injury in spontaneoushypertensive rats with diabetes. Chin Med J (Engl) 115: 972-978,2002.5 v3 y$ Q6 k* ?) {( r9 l) f
0 `0 @+ W4 Y  d# o8 q' v

Chen S, EvansT, Deng D, Cukiernik M, and Chakrabarti S. Hyperhexosemia inducedfunctional and structural changes in the kidneys: role of endothelins. Nephron 90:86-94, 2002.

% c% n1 }$ m4 v3 d

Chen Y, Sun Y,Lin J, Zhou A, and Wang H. Research on the mechanism of endothelininflammatory effects on human mesangial cells. Chin Med J(Engl) 110:530-534, 1997.

9 R. [: h6 c- F: ^
! x6 g# T% I, `+ l  s; M
Coroneos EJ,Kester M, Maclouf J, Thomas P, and Dunn MJ. Calcium-regulated proteintyrosine phosphorylation is required for endothelin-1 to induce prostaglandinendoperoxide synthase-2 mRNA expression and protein synthesis in mesangialcells. J Am Soc Nephrol 8:1080-1090, 1997.

; {. R) a4 k- [5 i
- X6 s- K2 v8 j
Derylo B,Babazono T, Glogowski E, Kapor-Drezgic J, Hohman T, and Whiteside C. Highglucose-induced mesangial cell altered contractility: role of the polyolpathway. Diabetologia 41:507-515, 1998.& W) p1 d: c1 e$ R
6 u& F2 V: S! d5 W8 y( l6 }- m

( p* I$ @" L9 N1 E$ @, K
Dhein S,Hochreuther S, Aus Dem Spring C, Bollig K, Hufnagel C, and Raschack M. Long-term effects of the endothelin(A) receptor antagonist LU 135252 and theangiotensin-converting enzyme inhibitor trandolapril on diabetic angiopathyand nephropathy in a chronic type I diabetes mellitus rat model. JPharmacol Exp Ther 293:351-359, 2000.- c3 E4 f  l- Z: I! P( Q' `

Duan SB, LiuFY, Luo JA, and Peng YM. Assessment of urinary endothelin-1 and nitricoxide levels and their relationship with clinical and pathologic types inprimary glomerulonephritis. Yonsei Med J 40: 425-429,1999.# B' m5 j2 |2 ]* f  n/ j. p
5 _9 J. C% h2 E3 r
; J: |+ T  v- H# m+ |
/ ^% ~7 V9 J- f4 s
Dulin N,Sorokin A, Reed E, Elliott S, Kehrl J, and Dunn M. RGS3 inhibits Gprotein-mediated signaling via translocation to the membrane and binding toG. Mol Cell Biol 19:714-723, 1999.
* r, v8 R# e3 b7 ]# Z4 T0 K0 r+ Q5 N

Ebihara I,Nakamura T, Tomino Y, and Koide H. Effect of a specific endothelinreceptor A antagonist and an angiotensin-converting enzyme inhibitor onglomerular mRNA levels for extracellular matrix components, metalloproteinases(MMP) and a tissue inhibitor of MMP in aminonucleoside nephrosis. Nephrol Dial Transplant 12:1001-1006, 1997.8 b4 i+ V0 R+ y2 I
! e: W+ Z. Q% b8 d; U9 V# `2 d

0 v7 y) t. I+ D3 _; v
Eto M,Barandier C, Rathgeb L, Kozai T, Joch H, Yang Z, and Luscher T. Thrombinsuppresses endothelial nitric oxide synthase and upregulatesendothelin-converting enzyme-1 expression by distinct pathways: role ofRho/ROCK and mitogen-activated protein kinase. CircRes 89:583-590, 2001.% G6 |" r4 m- x4 Y
/ z: o+ z7 s' O4 A& e; i
7 X7 `: y/ Z2 ^9 Y$ R; j

Feldman DL,Mogelesky TC, Chou M, and Jeng AY. Attenuation of puromycinaminonucleoside-induced glomerular lesions in rats by CGS 26303, a dualneutral endopeptidase/endothelin-converting enzyme inhibitor. JCardiovasc Pharmacol 36:S342-S345, 2000.
  |+ }$ }$ F6 X: L5 }

Foschi M, ChariS, Dunn M, and Sorokin A. Biphasic activation of p21ras by endothelin-1sequentially activates the ERK cascade and phosphatidylinositol 3-kinase. EMBO J 16:6439-6451, 1997.; n/ {- @* {$ q9 T/ Q

, m: b: R6 e! }3 n6 r
; T' ^4 \- L, l3 V7 V% a
Foschi M,Franchi F, Han J, La Villa G, and Sorokin A. Endothelin-1 induces serinephosphorylation of the adaptor protein p66Shc and its association with 14-3-3protein in glomerular mesangial cells. J Biol Chem 276: 26640-26647,2001.

Foschi M,Sorokin A, Pratt P, McGinty A, La Villa G, Franchi F, and Dunn M. Preproendothelin-1 expression in human mesangial cells: evidence for a p38mitogen-activated protein kinase/protein kinases-C-dependent mechanism. J Am Soc Nephrol 12:1137-1150, 2001.% w6 f. B$ U) h4 Q7 A$ s6 ~
0 B! z" U2 v) L: o, Z, a

Fukunaga M,Fujiwara Y, Ochi S, Yokoyama K, Shoji T, Fukuhara Y, Orita Y, Kamada T, BadrKF, and Ueda N. Mechanism of induction of prostaglandin E 2 production by endothelin 1 in cultured rat mesangial cells. ExpNephrol 4:340-349, 1996.( r9 ]  K8 t$ h5 a5 ?, e8 j# e( @

Gomez-Garre D,Largo R, Liu XH, Gutierrez S, Lopez-Armada MJ, Palacios I, and Egido J. Anorally active ETA/ETB receptor antagonist ameliorates proteinuria andglomerular lesions in rats with proliferative nephritis. KidneyInt 50:962-972, 1996.
5 ]1 `& o+ r& a; v5 h
3 w6 v- K1 K# i8 G+ r8 y1 h) e' o

Gomez-Garre D,Ruiz-Ortega M, Ortego M, Largo R, Lopez-Armada MJ, Plaza JJ, Gonzalez E, andEgido J. Effects and interactions of endothelin-1 and angiotensin II onmatrix protein expression and synthesis and mesangial cell growth. Hypertension 27:885-892, 1996.8 {" O1 _0 ?  ^; G7 ~9 @
5 _) V5 m9 B* `: d
' l' U7 L7 C/ x  L

Goodall T, KindCN, and Hammond TG. FK506-induced endothelin release by cultured ratmesangial cells. J Card Pharm 26, Suppl 3:S482-S485, 1995.
- Y% M8 N$ R. z. H" C: ^/ p/ F

' I4 c$ z" }& J/ F* U
Goruppi S,Bonventre J, and Kyriakis J. Signaling pathways and late-onset geneinduction associated with renal mesangial cell hypertrophy. EMBOJ 216:5427-5436, 2002.
& K' _* l. k" F$ ^" ^( p

3 y7 k2 X3 I6 O. [9 E) m# p2 H* Z
Hargrove GM,Dufresne J, Whiteside C, Muruve DA, and Wong NC. Diabetes mellitusincreases endothelin-1 gene transcription in rat kidney. KidneyInt 58:1534-1545, 2000.( q2 K0 T+ ~8 Z3 }( s% {
8 s" d% P- R4 X- N2 R

Herman WH,Emancipator SN, Rhoten RL, and Simonson MS. Vascular and glomerularexpression of endothelin-1 in normal human kidney. Am J PhysiolRenal Physiol 275:F8-F17, 1998.: y8 e* c* F) w8 t- s# c, i

# c2 p5 S$ e( b7 e' Z: P
9 F* M. j% |. t( f, \
Hirahashi J,Nakaki T, Hishikawa K, Marumo T, Yasumori T, Hayashi M, Suzuki H, and SarutaT. Endothelin-1 inhibits induction of nitric oxide synthase and GTPcyclohydrolase I in rat mesangial cells. Pharmacology 53: 241-249,1996.
+ `- ~) s1 T) L+ ~, [

) U. t/ _+ F0 p% C
Hiraoka J, AraiH, Yoshimasa T, Takaya K, Miyamoto Y, Yamashita J, Suga S, Ogawa Y, ShirakamiG, Itoh H, Yamori Y, and Nakao K. Augmented expression of the endothelin-Areceptor gene in cultured mesangial cells from strokeprone spontaneouslyhypertensive rats. Clin Exp Pharmacol Physiol Suppl 22: S191-S192,1995.
* n( |6 C: J1 f3 b9 X7 i! e* Z

# |  h" L( _* I$ P% @: ^$ C8 [
Hocher B,Schwarz A, Reinbacher D, Jacobi J, Lun A, Priem F, Bauer C, Neumayer HH, andRaschack M. Effects of endothelin receptor antagonists on the progressionof diabetic nephropathy. Nephron 87: 161-169,2001.

Hua H, GoldbergHJ, Fantus IG, and Whiteside CI. High glucose-enhanced mesangial cellextracellular signal-regulated protein kinase activation and 1 (IV) collagen expression in response to endothelin-1: roleof specific protein kinase C isozymes. Diabetes 50: 2376-2383,2001.* d6 ?( G4 m9 ?+ J0 i
* p! P+ P, E; r8 d/ w7 s9 G

4 b2 T5 N! L: m: }! v0 S
Hua H, Munk S,and Whiteside CI. Endothelin-1 activates mesangial cell ERK1/2 viaEGF-receptor transactivation and caveolin-1 interaction. Am JPhysiol Renal Physiol 284:F303-F312, 2003.

Hughes AK,Padilla E, Kutchera WA, Michael JR, and Kohan DE. Endothelin-1 inductionof cyclooxygenase-2 expression in rat mesangial cells. KidneyInt 47:53-61, 1995.

( }4 E9 Y/ W, v* X
Hughes AK,Stricklett PK, Padilla E, and Kohan DE. Effect of reactive oxygen specieson endothelin-1 production by human mesangial cells. KidneyInt 49:181-189, 1996.
. q. G2 A/ R& B. z/ d. w& E8 ?
; e* N- q. a1 g
/ s- _! `2 r* ~# I! R+ `7 H9 `
Humbert M andCabane J. Successful treatment of systemic sclerosis digital ulcers andpulmonary arterial hypertension with endothelin receptor antagonist bosentan. Rheumatology (Oxf) 42:191-193, 2003.

1 _% F6 n- x+ J9 {- y/ w( ], N/ K
Ikeda M, KohnoM, Horio T, Yasunari K, Yokokawa K, Kano H, Minami M, Hanehira T, Fukui T, andTakeda T. Effect of thrombin and PDGF on endothelin production in culturedmesangial cells derived from spontaneously hypertensive rats. ClinExp Pharmacol Physiol Suppl 22:S197-S198, 1995.5 C9 l! G% `# Y* v$ d
# c, |7 G% z) Z3 J+ T3 h
% N8 z) x1 M7 H: w3 Z, n8 I
$ o6 ~  b7 ^8 A: N( w$ `1 ^
Ikeda M, KohnoM, and Takeda T. Endothelin production in cultured mesangial cells ofspontaneously hypertensive rats. Hypertension 25: 1196-1201,1995.0 w. P9 ?& ]1 {, F" u( N5 @

9 v5 \+ c4 }. ?# r1 v0 a

Imamura T,Huang J, Dalle S, Ugi S, Usui I, Luttrell L, Miller W, Lefkowitz R, andOlefsky J. -Arrestin-mediated recruitment of the Src family kinaseYes mediates endothelin-1-stimulated glucose transport. J BiolChem 276:43663-43667, 2001.5 E  V7 y9 S9 T. \- D: d
' h% h# C* r& u5 _  w$ a

' a( S. C6 _6 s' T' A, C
Inoue A,Yanagisawa M, Takuwa Y, Mitsui Y, Kobayashi M, and Masaki T. The humanpreproendothelin-1 gene. J Biol Chem 264: 14954-14959,1989.
5 E2 U, l) j3 F5 n' M' u, q
" l6 u8 y8 C* B! j1 K
! B$ l" B5 `6 B  ~& s2 q0 n
Inui D,Yoshizumi M, Suzaki Y, Kirima K, Tsuchiya K, Houchi H, Kagami S, and TamakiT. Effect of endothelin-1(1-31) on p38 mitogen-activated proteinkinase in cultured human mesangial cells. Life Sci 68: 635-645,2000.& N; u1 q' z3 g: ?3 X* @9 n
. ^& s" [* k, e8 t3 E. c, \
* s4 F+ Q* [5 W0 d' R

Ishaque A, DunnM, and Sorokin A. Cyclooxygenase-2 inhibits TNFa-mediated apoptosis inrenal glomerular mesangial cells. J Biol Chem 278: 10629-10640,2003.

: D9 C! H8 W  S& S% A& p7 m

Iwamoto T,Tamaki K, Nakayama M, Okuda S, and Fujishima M. Effect of endothelin 1 onfibrinolysis and plasminogen activator inhibitor 1 synthesis in rat mesangialcells. Nephron 73:273-279, 1996.7 p! Z5 n+ X' N6 X. A. I0 ~
9 S' @- C8 {! m

3 ?' V% o# L( \' x) ], s2 X
Iwasaki S,Homma T, Matsuda Y, and Kon V. Endothelin receptor subtype B mediatesautoinduction of endothelin-1 in rat mesangial cells. J BiolChem 270:6997-7003, 1995.
. @) T8 I& J: J

Jaffer FE,Knauss TC, Poptic E, and Abboud HE. Endothelin stimulates PDGF secretionin cultured human mesangial cells. Kidney Int 38: 1193-1198,1990.

Jeng AY, MulderP, Kwan AL, and Battistini B. Nonpeptidic endothelin-converting enzymeinhibitors and their potential therapeutic applications. Can JPhysiol Pharmacol 80:440-449, 2002.

6 c6 c0 i  Z) q) u
2 {3 B  j2 Z3 p: [9 a, G
Kalra PR, MoonJC, and Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentanfor Lowering Cardiac Events in Heart Failure) study spell the end fornon-selective endothelin antagonism in heart failure? Int JCardiol 85:195-197, 2002.& H- n" Q) U# d: g9 ^9 Y

9 A/ P/ d) s! S* c
Kaluski E,Kobrin I, Zimlichman R, Marmor A, Krakov O, Milo O, Frey A, Kaplan S, KrakoverR, Caspi A, Vered Z, and Cotter G. RITZ-5: randomized intravenousTeZosentan (an endothelin-A/B antagonist) for the treatment of pulmonaryedema: a prospective, multicenter, double-blind, placebo-controlled study. J Am Coll Cardiol 41:204-210, 2003.
* r" o9 N6 x/ \2 K

4 q$ y6 |: I2 u" K1 V1 k
Karam H,Bruneval P, Clozel JP, Löffler BM, Bariéty J, and Clozel M. Role of endothelin in acute renal failure due to rhabdomyloysis in rats. J Pharm Exp Ther 274:481-486, 1995.8 E$ [/ B7 e% W
7 O; L, ]+ C# @: f+ t$ C
) j9 \! k; L, d+ M2 r% d; `

Kedzierski R and Yanagisawa M. Endothelin system: the double-edged sword in health anddisease. Annu Rev Pharmacol Toxicol 41: 851-876,2001.

# H) X* ]) t5 s7 b  I. p0 M

Kitamura A,Kagami S, Urushihara M, Kondo S, Yoshizumi M, Tamaki T, and Kuroda Y. Endothelin-1 is a potent stimulator of alpha1beta1 integrin-mediated collagenmatrix remodeling by rat mesangial cells. Biochem Biophys ResCommun 299:555-561, 2002.

Kitamura K,Shiraishi N, Singer W, Handlogten M, Tomita K, and Miller R. Endothelin-Breceptors activate G 13. Am J Physiol CellPhysiol 276:C930-C937, 1999.. V: h- _" ]& ^$ z$ ^/ P! y. C

! B5 o& ^0 J3 g0 m* {) t* W

Kohan D. Endothelins in the normal and diseased kidney. Am J KidDis 29:2-26, 1997.+ S; N8 W& B" `" Z

Kohan DE. Production of endothelin-1 by rat mesangial cells: regulation by tumornecrosis factor. J Lab Clin Med 119: 477-484,1992.
+ ?  L) {+ H; b7 `$ s* F# \% p

: r* m  y1 I2 y' e* e; _' V$ ]
Kohno M, HorioT, Ikeda M, Yokokawa K, Fukui T, Yasunari K, Kurihara N, and Takeda T. Angiotensin II stimulates endothelin-1 secretion in cultured rat mesangialcells. Kidney Int 42:860-866, 1992./ \0 I+ p* L: b' w

# n8 P) p* m# u6 ~2 W% Q

Kohno M, HorioT, Yokokawa K, Kurihara N, and Takeda T. C-type natriuretic peptideinhibits thrombin-and angiotensin II-stimulated endothelin release via cyclicguanosine 3',5'-monophosphate. Hypertension 19:320-325, 1992.1 C7 I7 M$ W9 p9 |) G) {1 g1 ~1 j
2 u+ [1 b$ {" X4 v7 }

Kohno M,Yokokawa K, Horio T, Ikeda M, Kurihara N, Mandal AK, and Takeda T. Heparininhibits endothelin-1 production in cultured rat mesangial cells. Kidney Int 45:137-142, 1994.  N6 P+ a$ v" T# L

Kohno M,Yokokawa K, Mandal AK, Horio T, Yasunari K, and Takeda T. Cardiacnatriuretic peptides inhibit cyclosporine-induced production of endothelin incultured rat mesangial cells. Metabolism 44: 404-409,1995.
$ [9 ^3 \% W, j+ C

2 X- w8 q  z  n9 |5 d
Krum H,Viskoper RJ, Lacourciere Y, Budde M, and Charlon V. The effect of anendothelin-receptor antagonist, bosentan, on blood pressure in patients withessential hypertension. Bosentan Hypertension Investigators. N EnglJ Med 338:784-790, 1998.

' t! N! C5 ~. @- N

Largo R,Gomez-Garre D, Liu XH, Alonso J, Blanco J, Plaza JJ, and Egido J. Endothelin-1 upregulation in the kidney of uninephrectomized spontaneouslyhypertensive rats and its modification by the angiotensin-converting enzymeinhibitor quinapril. Hypertension 29: 1178-1185,1997.: m: D  l" k+ g# r3 I

3 q; l* u8 `1 O
) h. V5 }- W; X. |6 |$ Q7 i
Lepailleur-Enouf D, Valdenaire O, Philippe M, Jandrot-Perrus M, andMichel J. Thrombin induces endothelin expression in arterial smooth musclecells. Am J Physiol Heart Circ Physiol 278: H1606-H1612,2000.* `1 D: w, s& L( b) @% K
& N: A' r: N4 ?1 N1 @
9 |$ S2 L# S* i
% m+ {9 B  c  L7 ^# @8 @
Lev S, MorenoH, Martinez R, Canoll P, Peles E, Musacchio J, Plowman G, Rudy B, andSchlessinger J. Protein tyrosine kinase PYK2 involved inCa 2 -induced regulation of ion channel and MAP kinasefunctions. Nature 376:737-745, 1995.( \% D0 @, f- z, s
+ T3 H+ h- a5 F# {/ }1 L
& O, [, |! b7 j6 N
3 B, @6 t; v; w3 V( |
Li M, Chen Y,Zhang Z, and Gao J. Inhibition of mesangial cell proliferation byantisense oligodeoxynucleotide targeting preproendothelin-1 mRNA in vitro. Chin Med J (Engl) 112:790-793, 1999.8 F8 h) _" s8 W! H8 F( v; |* y9 v
( K# a# H  V: N0 b  Q# x& V  g
* I5 y/ L' y3 _" c& G4 H
. B0 w* U! w7 |3 X* r
Louis A,Cleland JG, Crabbe S, Ford S, Thackray S, Houghton T, and Clark A. Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVERand RENAISSANCE and cachexia and cholesterol in heart failure. Highlights ofthe Scientific Sessions of the American College of Cardiology, 2001. Eur J Heart Fail 3:381-387, 2001.$ B8 j# P5 S: N" \  \) D$ M
$ z: u8 |1 L, M/ C
$ [6 |' e( I& q2 r

Luscher TF,Enseleit F, Pacher R, Mitrovic V, Schulze MR, Willenbrock R, Dietz R, RoussonV, Hurlimann D, Philipp S, Notter T, Noll G, and Ruschitzka F. Hemodynamicand neurohumoral effects of selective endothelin A [ET(A)] receptor blockadein chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial(HEAT). Circulation 106:2666-2672, 2002.
+ T& F$ E; r* C" F8 Z' T

Martinez M,Randriamboavonjy V, Ohlmann P, Komas N, Duarte J, Schneider F, Stoclet J, andAndriantsitohaina R. Involvement of protein kinase C, tyrosine kinases,and Rho kinase in Ca 2 handling of human small arteries. Am J Physiol Heart Circ Physiol 279: H1228-H1238,2000.
/ B  w+ E* A# \& x9 a' T/ j. J

Migliaccio E,Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi P, Lanfrancone L, andPelicci P. The p66shc adaptor protein controls oxidative stress responseand life span in mammals. Nature 402: 309-313,1999.  c! X% C4 h- i' _& A$ w6 A0 W
) X' L0 z" F' t  ~, T

* R# }" y+ ^& `: e1 x( @
Morimoto T,Hasegawa K, Wada H, Kakita T, Kaburagi S, Yanazume T, and Sasayama S. Calcineurin-GATA4 pathway is involved in beta-adrenergic agonist-responsiveendothelin-1 transcription in cardiac myocytes. J BiolChem 276:34983-34989, 2001.
$ G0 y- I3 t2 S' j( A, ?

Murugesan N, GuZ, Spergel S, Young M, Chen P, Mathur A, Leith L, Hermsmeier M, Liu EC, ZhangR, Bird E, Waldron T, Marino A, Koplowitz B, Humphreys WG, Chong S, MorrisonRA, Webb ML, Moreland S, Trippodo N, and Barrish JC. Biphenylsulfonamideendothelin receptor antagonists. 4. Discovery of N -[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]- N,3,3-trimethylbutanamide(BMS-207940), a highly potent and orally active ET A selectiveantagonist. J Med Chem 46:125-137, 2003.7 [  v" `( P" m, b8 c

# |4 i" T4 o+ p9 r( r
9 Z0 x  c" V$ _* u' |0 g- z- e
Mylona P andCleland JG. Update of REACH-1 and MERIT-HF clinical trials in heartfailure. Cardio net Editorial Team. Eur J Heart Fail 1: 197-200,1999.
) q* m! f5 k7 I/ g; q) R1 H, T
0 @) |4 K0 p* I
- r* p6 w# B9 k
Nakamura T,Ebihara I, Fukui M, Tomino Y, and Koide H. Effect of a specific endothelinreceptor A antagonist on mRNA levels for extracellular matrix components andgrowth factors in diabetic glomeruli. Diabetes 44: 895-899,1995.

9 @- N: n& }) r) w$ ^: N
Nakov R, PfarrE, and Eberle S. Darusentan: an effective endothelin A receptor antagonistfor treatment of hypertension. Am J Hypertens 15: 583-589,2002.2 p- s0 E6 j9 [5 J
- F8 X. p& X; G6 A

- }9 e$ T/ R: n% Z: h3 c
Nambi P, GellaiM, Wu HL, and Prabhakar U. Upregulation of osteopontin in ischemia-inducedrenal failure in rats: a role for ET-1? Biochem Biophys ResCommun 241:212-214, 1997.
; l0 A5 r6 W  n) W" w# U8 ~/ H) h0 v
5 I7 s2 `  c$ Z2 _: z0 R, _: q0 i

Nord EP. Role of endothelin in acute renal failure. Blood Purif 15: 273-285,1997.  u3 `/ j! n5 v/ ?- S7 [
- u/ L( }5 H! o6 H6 C% y

  k% H( J7 Z) C3 e
Nutt LK andO'Neil RG. Effect of elevated glucose on endothelin-induced store-operatedand non-store-operated calcium influx in renal mesangial cells. JAm Soc Nephrol 11:1225-1235, 2000.1 N: ^+ `( Z: ~5 g
& ~+ p( h! [7 S5 Y8 f# J
) c6 e" M8 Z( d: d
7 s5 A5 o. E$ T( a0 |( o6 ]% k
Orth SR, AmannK, Gehlen F, Unger L, Wagner J, Raschack M, and Ritz E. Adult humanmesangial cells (HMCs) express endothelin-B-receptors which mediateendothelin-1-induced cell growth. J CardiovascPharmacol 36:S232-S237, 2000.

& x6 m3 q; I. y
! n8 H0 G7 R1 v. I7 h' t
Owada A, TomitaK, Terada Y, Sakamoto H, Nonguchi H, and Marumo F. Endothelin (ET)-3stimulates cyclic guanosine 3',5'-monophosphate production via ETBreceptor by producing nitric oxide in isolated rat glomerulus, and in culturedrat mesangial cells. J Clin Invest 93: 556-563,1994.3 ?- k7 s' K* R
4 {9 V2 U6 ^+ K' ^6 I1 m

6 j* j# A) t4 \2 v; F5 J
Parameswaran N,Hall CS, Boeck BC, Sparks HV, Gallo KA, and Spielman WS. Mixed lineagekinase 3 inhibits platelet-derived growth factor-stimulated DNA synthesis andmatrix mRNA expression in mesangial cells. Cell PhysiolBiochem 12:325-334, 2002.
% _3 D& }6 ^+ `) g. j( p' @
" k: @- A5 ]% J, S7 I! n: S5 w

Pearson G,Robinson F, Beers G, Xu B, Karandikar M, Berman K, and Cobb M. Mitogen-activated protein (MAP) kinase pathways: regulation and physiologicalfunctions. Endocr Rev 22:153-183, 2001.

5 K' h' ~% M% m' L2 k
Pelicci G,Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I,Grignani F, Pawson T, and Pelicci P. A novel transforming protein (SHC)with an SH2 domain is implicated in mitogenic signal transduction. Cell 70:93-104, 1992.

Remuzzi G,Perico N, and Benigni A. New therapeutics that antagonize endothelin:promises and frustrations. Nat Rev 1: 986-1001,2002.
" q8 E! M& d: S! i9 r6 m
9 i+ A. k# b# R8 r2 F4 Q  L) ~1 z# `# U

Rubin LJ,Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S,Leconte I, Landzberg M, and Simonneau G. Bosentan therapy for pulmonaryarterial hypertension. N Engl J Med 346: 896-903,2002.

0 u2 s/ ]" `: ]
. ?" N5 l7 l1 V/ {+ H
Ruiz-Ortega M,Gomez-Garre D, Liu XH, Blanco J, Largo R, and Egido J. Quinapril decreasesrenal endothelin-1 expression and synthesis in a normotensive model ofimmune-complex nephritis. J Am Soc Nephrol 8: 756-768,1997.9 Q+ n( D* t7 z! P- U- w
# _0 k, M: B( j+ _

/ F9 R# {  Y8 C* x# o
Sakamoto H,Sasaki S, Nakamura Y, Fushimi K, and Marumo F. Regulation of endothelin-1production in cultured rat mesangial cells. Kidney Int 41: 350-355,1992.% \0 v9 g+ c5 F: ?

) {3 K: R  l- n0 O4 i

Shaw MD,Vermeulen M, Murray GD, Pickard JD, Bell BA, and Teasdale GM. Efficacy andsafety of the endothelin, receptor antagonist TAK-044 in treating subarachnoidhemorrhage: a report by the Steering Committee on behalf of theUK/Netherlands/Eire TAK-044 Subarachnoid Haemorrhage Study Group. JNeurosurg 93:992-997, 2000.2 W, U6 |& d9 l- r$ @$ [

Shindo T,Kurihara H, Maemura K, Kurihara Y, Ueda O, Suzuki H, Kuwaki T, Ju KH, Wang Y,Ebihara A, Nishimatsu H, Moriyama N, Fukuda M, Akimoto Y, Hirano H, Morita H,Kumada M, Yazaki Y, Nagai R, and Kimura K. Renal damage and salt-dependenthypertension in aged transgenic mice overexpressing endothelin-1. JMol Med 80:105-116, 2002.

( ~' Y5 E! [6 ]* d1 u
" t5 O2 ^% k* }7 ~9 l4 {( I8 v6 p
Simonson M andDunn MJ. Endothelin-1 stimulates contraction of rat glomerular mesangialcells and potentiates -adrenergic-mediated cyclic adenosinemonophosphate accumulation. J Clin Invest 85: 790-797,1990.# R( m9 X) M" j% J3 ~

- [9 L. z5 E& f( |9 i' v7 s* q

Simonson M,Jones J, and Dunn M. Cytosolic and nuclear signaling by endothelinpeptides: mesangial response to glomerular injury. KidneyInt 41:542-545, 1992.

Simonson MS. Endothelins: multifunctional renal peptides. Physiol Rev 73:375-411, 1993.$ X( |7 D+ g. J  k, o5 G5 ?1 S

; W% t* C' r% |% B$ Q

Simonson MS andDunn MJ. Ca2  signaling by distinct endothelin peptides in glomerularmesangial cells. Exp Cell Res 192: 148-156,1991.
" p+ ?( p  f! l2 o
0 [/ x- M) r* o' [( k
- H  s$ b/ x* Y% U/ b4 r# S
Simonson MS andDunn MJ. Cellular signaling by peptides of the endothelin gene family. FASEB J 4:2989-3000, 1990.

Simonson MS andRooney A. Characterization of endothelin receptors in mesangial cells:evidence for two functionally distinct endothelin binding sites. Mol Pharmacol 46:41-50, 1994.# e9 [2 e. W) _0 g! V: z

Simonson MS,Wann S, Mene P, Dubyak GR, Kester M, and Dunn MJ. Endothelin-1 activatesthe phosphoinositide cascade in cultured glomerular mesangial cells. J Cardiovasc Pharmacol 13:S80-S84, 1989.

* h7 I! h, t9 }* ?

Simonson MS,Wann S, Mene P, Dubyak GR, Kester M, Nakazato Y, Sedor JR, and Dunn MJ. Endothelin stimulates phospholipase C, Na /H exchange,c-fos expression, and mitogenesis in rat mesangial cells. J ClinInvest 83:708-712, 1989.

Sorokin A,Kozlowski P, Graves L, and Philip A. Proteintyrosine kinase Pyk2 mediatesendothelin-induced p38 MAPK activation in glomerular mesangial cells. J Biol Chem 276:21521-21528, 2001.

4 K/ g- I2 }' e5 }; O
" u6 f0 [' S! u& e9 H8 J# u4 L
Sugimoto K,Tsuruoka S, and Fujimura A. Renal protective effect of YM598, a selectiveendothelin ET A receptor antagonist, against diabetic nephropathy inOLETF rats. Eur J Pharmacol 450: 183-189,2002.6 j0 S) t2 n# s( c, x$ h
2 w( [0 f# f( d% f$ b- E* Z" n

Sugimoto T,Haneda M, Sawano H, Isshiki K, Maeda S, Koya D, Inoki K, Yasuda H,Kashiwagi A, and Kikkawa R. Endothelin-1 induces cyclooxygenase-2expression via nuclear factor of activated T-cell transcription factor inglomerular mesangial cells. J Am Soc Nephrol 12: 1359-1368,2001.

Takeda M,Breyer MD, Noland TD, Homma T, Hoover RL, Inagami T, and Kon V. Endothelin-1 receptor antagonist: effects on endothelinandcyclosporine-treated mesangial cells. Kidney Int 42: 1713-1719,1992.
6 D! q  y# [& A, I, R, H6 w' x" \* G2 J

8 Y2 u$ ^% H* x! {: p
Takeda M,Iwasaki S, Hellings SE, Yoshida H, Homma T, and Kon V. Divergentexpression of EtA and EtB receptors in response to cyclosporine in mesangialcells. Am J Pathol 144:473-479, 1994.
5 \% l* b* L& o' Y8 v

Tan MS, Lee YJ,Shin SJ, and Tsai JH. Oxidized low-density lipoprotein stimulatesendothelin-1 release and mRNA expression from rat mesangial cells. J Lab Clin Med 129:224-230, 1997.
$ ^0 @/ j6 s& V# {
# S1 k! [- ^+ P/ ?
: ?1 q# y% z6 x$ |
Terada Y,Inoshita S, Nakashima O, Yamada T, Tamamori M, Ito H, Sasaki S, and MarumoF. Cyclin D1, p16, and retinoblastoma gene regulate mitogenic signaling ofendothelin in rat mesangial cells. Kidney Int 53: 76-83,1998.. ^- C/ w* a' o+ N' n# r, d6 I
# I$ {0 X7 R9 n9 q! b% d, T
7 Q! F$ ?% b. `

Tian W, ZhangZ, and Cohen D. MAPK signaling and the kidney. Am J PhysiolRenal Physiol 279:F593-F604, 2000.; Z* x9 T( b. M3 m
; M2 c- r4 U, w: q2 x+ y% D! G
: \9 f4 S. F. t, q5 W% ~0 b( b

Tojo A, FujitaT, and Wilcox CS. Omapatrilat: still a promise in salt-sensitivehypertension? J Hypertens 21:31-32, 2003.
; |9 f0 V( }- s7 B: g% J8 y+ O

2 ?: r' y, X1 e1 ?  }6 `
Tolloczko B,Tao F, Zacour M, and Martin J. Tyrosine kinase-dependent calcium signalingin airway smooth muscle cells. Am J Physiol Lung Cell MolPhysiol 278

1138-L1145, 2000.
  J* ^, d1 f; J, S8 n; s0 M1 [

Tsiani E, LekasP, Fantus IG, Dlugosz J, and Whiteside C. High glucose-enhanced activationof mesangial cell p38 MAPK by ET-1, ANG II, and platelet-derived growthfactor. Am J Physiol Endocrinol Metab 282: E161-E169,2002.+ U4 W0 y& C( U' ]5 }2 x4 M& j' q

+ |3 ?, h/ t" K! h# T0 p4 T  z7 L& R

Vemulapalli S,Chintala M, Stamford A, Watkins R, Chiu P, Sybertz E, and Fawzi A. Renal effects of SCH 54470: a triple inhibitor of ECE, ACE, and NEP. Cardiovasc Drug Rev 15:260-272, 1997.
7 I% i1 a9 o) C" T& v( C
$ L: A! c4 F' d; e/ o& f
' v0 k  R6 U3 h/ O
Wang Y, MishraR, and Simonson M. Ca 2 /calmodulin-dependent proteinkinase II stimulates c-fos transcription and DNA synthesis by a Src-basedmechanism in glomerular mesangial cells. J Am SocNephrol 14:28-36, 2003.+ V. _; e; \3 _9 b8 i
! K6 P6 ~5 _  t+ i$ a8 b3 P
6 W. V7 s6 {' F3 Y

Wang Y,Simonson MS, Pouyssegur J, and Dunn MJ. Endothelin rapidly stimulatesmitogen-activated protein kinase activity in rat mesangial cells. Biochem J 287:589-594, 1992.
6 b% K" z: ^/ k0 F2 p4 }

Watts S. 5-Hydroxytryptamine-induced potentiation of endothelin-1- andnorepinephrine-induced contraction is mitogen-activated protein kinase pathwaydependent. Hypertension 35:244-248, 2000.

0 K( C! D5 C8 r$ t- f
% v; z+ ]# n5 V2 m1 B# z
Whiteside C andDlugosz J. Mesangial cell protein kinase C isozyme activation in thediabetic milieu. Am J Physiol Renal Physiol 282: F975-F980,2002.6 U  t5 t6 t2 S# J8 m; A
6 \% f: T0 @8 M* b; I0 f

; Y/ z6 X, D/ }* h! E: }
Yamashita K,Discher D, Hu J, Bishopric N, and Webster K. Molecular regulationof the endothelin-1 gene by hypoxia. Contributions of hypoxia-induciblefactor-1, activator protein-1, GATA-2, AND p300/CBP. J BiolChem 276:12645-12653, 2001.

Yanagisawa M,Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, andMasaki T. A novel potent vasoconstrictor peptide produced by vascularendothelial cells. Nature 332:411-415, 1988.

8 z+ O& q% {* }' q4 E2 E: |

Yao J, MoriokaT, Li B, and Oite T. Endothelin is a potent inhibitor of matrixmetalloproteinase-2 secretion and activation in rat mesangial cells. Am J Physiol Renal Physiol 280:F628-F635, 2001.

  D9 R+ L, a4 }+ `, C* {! t

Yokokawa K,Kohno M, Johchi M, Horio T, Murakawa K, Yasunari K, Yanagisawa M, andTakeda T. Effect of endothelin receptor antagonist, BQ-123, onCa 2 signaling in cultured rat mesangial cells. Life Sci 53:1631-1641, 1993.
- j" q8 g1 M2 C7 e$ b

6 M+ }" f0 l  H1 }* S
Yoshimura A,Iwasaki S, Inui K, Ideura S, Koshikawa S, Yanagisawa M, and MasakiT. Endothelin-1 and endothelin B type receptor are induced in mesangialproliferative nephritis in the rat. Kidney Int 48: 1290-1297,1995.0 x; r' w! u+ U: C7 Y
- d; ]' p: L' v4 y. n) o

Zhou L, Ida T,and Marumo F. Role of thromboxane A 2, endothelin-1 andendothelin-3 in rat nephrotoxic serum nephritis. Tohoku J ExpMed 178:357-369, 1996.0 u- l& ]8 `% S/ ]  T4 j: I

9 I( Q6 ?  N+ j2 _$ H6 E8 n
Zoja C, OrisioS, Perico N, Benigni A, Morigi M, Benatti L, Rambaldi A, and RemuzziG. Constitutive expression of endothelin gene in cultured human mesangialcells and its modulation by transforming growth factor-, thrombin, and athromboxane A 2 analogue. Lab Invest 64: 16-20,1991.' S) f3 w: q' T; _% J1 A. ^
! D+ B. O0 p: Q$ b0 l& ~

Zubkov A,Rollins K, Parent A, Zhang J, and Bryan R Jr. Mechanism ofendothelin-1-induced contraction in rabbit basilar artery. Stroke 31:526-533, 2000.

收藏0 分享0 顶0 踩0