Cell biology and molecular mechanisms of injury in ischemic acute renal failure

Current Opinion in Nephrology and Hypertension

Volumn 9, Issue 4, 2000, Pages 427-434

  Sheridan, Alice M ^a   Bonventre, Joseph V ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL ADHESION MOLECULE; CHEMOKINE; ENDOTHELIN 1; INTEGRIN; INTERLEUKIN 1; NITRIC OXIDE; REACTIVE OXYGEN METABOLITE; SELECTIN; TUMOR NECROSIS FACTOR ALPHA;

ACUTE KIDNEY FAILURE; APOPTOSIS; CELL INFILTRATION; ENDOTHELIUM; GLOMERULUS FILTRATION RATE; HUMAN; KIDNEY PROXIMAL TUBULE; LEUKOCYTE; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; RAT; REVIEW; VASOCONSTRICTION;

ANIMALS; APOPTOSIS; HEMODYNAMIC PROCESSES; HUMANS; ISCHEMIA; KIDNEY; KIDNEY FAILURE, ACUTE; KIDNEY TUBULES, PROXIMAL; LEUKOCYTES; RENAL CIRCULATION;

EID: 0033936194     PISSN: 10624821     EISSN: None     Source Type: Journal    
DOI: 10.1097/00041552-200007000-00015     Document Type: Review

References (95)

1. 1 Bonventre JV. Mechanisms of ischemic acute renal failure. Kidney Int 1993; 43:1160-1178.
2. 2 Zuk A, Bonventre JV, Brown D, Matlin KS. Polarity, integrin, and extracellular matrix dynamics in the postischemic rat kidney. Am J Physiol 1998; 275:C711-C731.
3. 3 Alejandro VSJ, Nelson WJ, Huie P, et al. Postischemic injury, delayed function and Na/K-ATPase distribution in the transplanted kidney. Kidney Int 1995; 48:1308-1315.
4. 4 Kwon O, Corrigan G, Myers BD, et al. Sodium absorption and distribution of Na+/K+-ATPase during postischemic injury to the renal allograft. Kidney Int 1999; 55:963-975. This is a follow-up study to one published in 1995 (Kidney Int 1995; 48:1308) of newly transplanted allograft recipients, which demonstrated: (i) abnormal proximal tubule distribution of sodium/potassium ATPase; and (ii) a marked increase in fractional sodium excretion. Both of these findings were predictive of delayed graft function. The authors suggest the possibility that stimulation of tubuloglomerular feedback by enhanced tubular sodium delivery to the macula densa contributes to the decreased GFR. Enhanced sodium delivery is caused by maldistribution of sodium/potassium ATPase. In the present study, the authors confirm their observation that reperfusion of a cadaveric allograft is accompanied by an increase in fractional sodium excretion that is much larger than that which would be expected with the administration of diuretics. To support their hypothesis of tubuloglomerular feedback activation further, the authors measured the fractional excretion of lithium, reasoning that, in order to affect tubuloglomerular feedback, the loss in sodium reabsorption must occur upstream of the macula densa. Lithium fractional excretion was doubled in allograft recipients. The proximal tubule undergoes the greatest change in the distribution of sodium/potassium ATPase.
5. 5 Vetterlein F, Petho A, Schmidt G. Distribution of capillary blood flow in rat kidney during post ischemic renal failure. Am J Physiol 1986; 251:H510-H519.
6. 6 Shibouta Y, Suzuki N, Shino A, et al. Pathophysiologic role of endothelin in acute renal failure. Life Sci 1990; 46:1611-1618.
7. 7 Gellai M, Jugus M, Fletcher T, et al. Reversal of postischemic acute renal failure with a selective endothelin receptor antagonist in the rat. J Clin Invest 1994; 93:900-906.
8. 8 Chan L, Chittinandana A, Shapiro JI, et al. Effect of an endothelin-receptor antagonist on ischemic acute renal failure. Am J Physiol 1994; 266:F135-F138.
9. 9 Mino N, Kobayashi M, Nakajima A, et al. Protective effect of a selective endothelin receptor antagonist, BQ-123, on ischemic acute renal failure in rats. Eur J Pharmacol 1992; 221:77-83.
10. 125I-labelled endothelin-1.
11. 11 Abassi ZA, Tate JE, Golomb E, Keiser HR. Role of neutral endopeptidases in the metabolism of endothelin. Hypertension 1992; 20:89-95.
12. 12 Nambi P, Pullen M, Wu HL, et al. Down regulation of kidney neutral endopeptidase mRNA, protein and activity during acute renal failure: possible mechanisms for ischemia-induced acute renal failure in rats? Mol Cell Biochem 1999; 197:53-59. NEP is involved in the degradation of endothelin. This study demonstrates a decrease in NEP activity 2-24 h after ischemia. The decrease in NEP activity was accompanied by a decrease in protein mass and by decreased mRNA demonstrated by Northern analysis. The changes in mRNA were detected immediately after ischemia.
13. 13 Zouki C, Baron C, Fournier A, Filep JG. Endothelin-1 enhances neutrophil adhesion to human coronary artery endothelial cells: role of ET(A) receptors and platelet-activating factor. Br J Pharmacol 1999; 127:969-979. Endothelin-1 enhances neutrophil adhesion to LPS and to human coronary endothelial cells. Blocking the endothelin A receptor but not the endothelin B receptor prevents this response as did a PAF antagonist. These data suggest that this effect is probably mediated via the generation of PAF through the activation of endothelin A receptors.
14. 14 Sanz MJ, Johnston B, Issekutz A, Kubes P. Endothelin causes P-selectin-dependent leukocyte rolling and adhesion within rat mesenteric microvessels. Am J Physiol 1999; 277:H1823-H1830. This study shows an increase in leukocyte rolling and adhesion but not emigration with infusion of endothelin-1. This effect was abrogated by anti-rat P-selectin monoclonal antibody. A mechanical reduction in blood flow comparable to that induced by endothelin infusion did not replicate these data, suggesting a direct effect of endothelin-1 rather than shear stress. These data support the direct role of endothelin-1 in the regulation of neutrophil adhesion.
15. 15 Peters H, Border WA, Noble NA. From rats to man: a perspective on dietary I-arginine supplementation in human renal disease. Nephrol Dial Transplant 1999; 14:1640-1650. The authors review the roles of NO, including neurotransmission, vasodilation, inflammation and cell phenotype regulation. This paper provides an excellent review of the cytotoxic effects of NO at high concentration via its irreversible reaction with superoxide anion.
16. 16 Kourembanas S, McQuillan LP, Leung GK, Faller DV. Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest 1993; 92:99-104.
17. 17 Richard V, Hogie M, Clozel M, et al. In vivo evidence of an endothelin-induced vasopressor tone after inhibition of nitric oxide synthesis in rats. Circulation 1995; 91:771-775.
18. 18 Noiri E, Peresleni T, Miller F, Goligorsky MS. In vivo targeting of inducible NO synthase with oligodeoxynucleotides protects rat kidney against ischemia. J Clin Invest 1996; 97:2377-2383.
19. 19 Liang M, Knox FG. Nitric oxide enhances the paracellular permeability of opossum kidney cells. Kidney Int 1999; 55:2215-2223. Sodium nitroprusside increases the paracellular permeability of opossum kidney cells. This was associated with a marked reduction in cell ATP (to 41% of control) and accompanied by an increase in lipid peroxidation. Antioxidants blunted this response and NO scavengers blocked the response. There was no decrease in cell viability as assessed by LDH release.
20. 20 Wangsiripaisan A, Gengaro PE, Nemenoff RA, et al. Effect of nitric oxide donors on renal tubular epithelial cell-matrix adhesion. Kidney Int 1999; 55:2281-2288. A metabolite of NO, peroxynitrite (ONOO-) but not NO, markedly decreases the adhesion of LLC-PK1, BSC-1 and opossum kidney cells on collagen type IV, collagen type I and fibronectin. This effect of ONOO - was dose dependent and was reversed by scavengers of NO and ONOO - and superoxide. These studies suggest that the metabolite of NO, rather than NO itself affects the adhesion of renal cells.
21. 21 Ling H, Edelstein C, Gengaro P, et al. Attenuation of renal ischemia-reperfusion injury in inducible nitric oxide synthase knockout mice. Am J Physiol 1999; 277:F383-390. Six to 8 week old NOS II knockout animals were subjected to 26 min of bilateral clamp followed by 24 and 48 h of reperfusion. Creatinines were decreased in the knockout animals at 24 (1.21 ± 0.25 versus 2.28 ± 0.38) and 48 h (0.96 ± 0.25 versus 2.0 ± 18). Less severe histological injury was observed in the knockout animals compared to wild type. NO protein was not induced by ischemia in wild-type animals, nor was tyrosine nitration increased in wild-type mice after ischemia reperfusion. HSP-72 (inducible) and HSP-73 (constitutive) were measured by immunoblot analysis. HSP-72 was upregulated in the wild-type and knockout animals after ischemia. In the knockout animals, however, basal levels of HSP-72 were also upregulated, whereas HSP-73 was unchanged.
22. 22 Yokoo T, Kitamura M. Heat shock proteins in the kidney. Exp Nephrol 1997; 5:439-444.
23. 23 Ruschitzka F, Shaw S, Noll G, et al. Endothelial vasoconstrictor prostanoids, vascular reactivity, and acute renal failure. Kidney Int 1998; 54:S-199-S-201.
24. 24 Linas SL, Shanley PF, Whittenburg D, et al. Neutrophils accentuate ischemia-reperfusion injury in isolated perfused rat kidneys. Am J Physiol 1988; 255:F728-F735.
25. 25 Willinger CC, Schramek H, Pfaller K, Pfaller W. Tissue distribution of neutrophils in postischemic acute renal failure. Virchows Arch B Cell Pathol Incl Mol Pathol 1992; 62:237-243.
26. 26 Heinzelmann M, Mercer-Jones MA, Passmore JC. Neutrophils and renal failure. Am J Kid Dis 1999; 34:384-399. This is a review of the role of neutrophils in acute renal failure. The authors delineate mechanisms by which neutrophils cause tissue destruction and pathways resulting in ROS generation. The biology of chemokines and adhesion molecules is reviewed.
27. 27 Klausner JM, Paterson IS, Goldman G, et al. Postischemic renal injury is mediated by neutrophils and leukotrienes. Am J Physiol 1989; 256:F794-F802.
28. 28 Hellberg PO, Kallskog TO. Neutrophil-mediated post-ischemic tubular leakage in the rat kidney. Kidney Int 1989; 36:555-561.
29. 29 Takada M, Nadeau KC, Shaw GD, et al. The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand. J Clin Invest 1997; 99:2682-2690.
30. 30 De Greef KE, Ysebaert DK, Ghielli M, et al. Neutrophils and acute ischemia-repertusion injury. J Nephrol 1998; 11:110-122.
31. 31 Paller MS. Effect of neutrophil depletion on ischemic renal injury in the rat. J Lab Clin Med 1989; 113:379-386.
32. 32 Kelly KJ, Williams WWJ, Colvin RB, Bonventre JV. Antibody to intercellular adhesion molecule-1 protects the kidneys against ischemic injury. Proc Natl Acad Sci USA 1994; 91:812-816.
33. 33 Kelly KJ, Williams WWJ, Colvin RB, et al. Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest 1996; 97:1056-1063.
34. 34 Molitoris BA, Marrs J. The role of adhesion molecules in ischemic acute renal failure. Am J Med 1999; 106:583-592. The authors review the role of adhesion molecules and neutrophil recruitment in ischemic-reperfusion injury. The authors also review the structure and function of tight junctions and adherens junctions.
35. 35 Rahman A, Kefer J, Bando, et al. E-selectin expression in human endothelial cells by TNF-α-induced oxidant generation and NF-κB activation. Am J Physiol 1998; 275:L533-L544.
36. 36 Donnahoo KK, Meng X, Ayala A, et al. Early kidney TNFα expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Physiol 1999; 277:R922-R929. This study demonstrates that 30 min of ischemia in the rat induced renal TNF mRNA and increased TNF protein and bioactivity (measured by cytotoxicity). TNF binding protein decreased TNF bioactivity, and neutrophil infiltrate as assessed by myeloperoxidase. TNF binding protein mitigated injury induced by ischemia-reperfusion (as assessed by serum creatinine). These data suggest that TNF evolution may be an early event in ischemia-reperfusion injury.
37. 37 Safirstein R, Megyesi J, Saggi SJ, et al. Expression of cytokine-like genes JE and KC is increased during renal ischemia. Am J Physiol 1991; 261:F1095-F1101.
38. 38 Hellberg PO, Bayat A, Kallskog O, Wolgast M. Red cell trapping after ischemia and long-term kidney damage. Influence of hematocrit. Kidney Int 1990; 37:1240-1247.
39. 39 Lieberthal W. Biology of acute renal failure: therapeutic implications. Kidney Int 1997; 52:1102-1115.
40. 40 Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med 1996; 334:1448-1460.
41. 41 Fanning AS, Mitic LL, Anderson JM. Transmembrane proteins in the tight junction barrier. J Am Soc Nephrol 1999; 10:1337-1345. The authors review the functional characteristics of tight junctions, specifically mechanisms mediating paracellular permeability and permselectivity. The authors review the structure of tight junctions, including descriptions of the proteins occludin, claudin and junction adhesion molecule.
42. 42 Claude P. Morphologic factors influencing transepithelial permeability: a model for resistance of the zonula occludens. J Membr Biol 1978; 39:219-232.
43. 43 Schwartz JH, Shih T, Menza SA, Lieberthal W. ATP depletion increases tyrosine phosphorylation of β-catenin and plakoglobin in renal tubular cells. J Am Soc Nephrol 1999; 10:2297-2305. ATP depletion of mouse proximal tubule cells increases tyrosine phosphorylation of β-catenin and plakoglobin. Although tyrosine phosphatase inhibitor (vanadate) reproduced the effect of ATP depletion in ATP replete cells (in that it increased tyrosine phosphorylation and decreased TER), genistein, an inhibitor of tyrosine kinase, decreased the ATP-depletion-induced tyrosine phosphorylation and ameliorated the decrease in TER. These data suggest that tyrosine phosphorylation of catenins induced by ATP depletion contributes to the loss of function of the junctional complex.
44. 44 Goligorsky MK, Lieberthal W, Racusen L, Simon E. Integrin receptors in renal tubular epithelium: new insights into pathophysiology of acute renal failure. Am J Physiol 1993; 264:F1-F8.
45. 45 Goligorsky MK, Dibona D. Pathogenetic role of Arg-Gly-Asp-recognizing integrins in acute renal failure. Proc Natl Acad Sci USA 1993; 90:5700-5704.
46. 46 Kroshin VM, Sheridan AM, Lieberthal W. Functional and cytoskeletal changes induced by sublethal injury in proximal tubular epithelial cells. Am J Physiol 1994; 266:F21-F30.
47. 47 Lieberthal W, McKenney J, Kiefer C, et al. β Integrin-mediated adhesion between renal tubular cells following anoxic injury. J Am Soc Nephrol 1997; 8:175-183.
48. 48 Noiri E, Gailit J, Sheth D, et al. Cyclic RGD peptides ameliorate ischemic acute renal failure in rats. Kidney Int 1994; 46:1050-1058.
49. 49 Vasco KA, Dewall RA, Riley AM. Effect of allopurinol in renal ischemia. Surgery 1972; 71:787-790.
50. 50 Paller MS, Hedlund BE. The role of iron in postischemic renal failure. Kidney Int 1988; 34:474-480.
51. 2 in mitochondria enriched with n-3 fatty acids. Proc Natl Acad of Sci USA 1990; 87:8845-8849.
52. 52 Kako K, Kato M, Matsuoka T, Mustapha A. Depression of membrane-bound Na/K-ATPase activity induced by free radicals and by ischemia of the kidney. Am J Physiol 1988; 254:C330-337.
53. 53 Chatterjee PK, Cuzzocrea S, Thiemermann C. Inhibitors of poly (ADP-ribose) synthetase protect rat proximal tubules against oxidant stress. Kidney Int 1999; 56:973-984.
54. 54 Berger NA. Poly (ADP-ribose) in the cellular response to DNA damage. Rad Res 1985; 101:4-15.
55. 2 but not apoptosis. Gastroenterology 1995; 109:472-482.
56. 56 Heller B, Wang ZQ, Wagner EF, et al. Inactivation of the poly (ADP-ribose) polymerase gene affects oxygen radical and nitric oxide toxicity in islet cells. J Biol Chem 1995; 270:11176-11180.
57. 57 Thiermermann C, Bowes J, Myint FP, Vane JR. Inhibition of the activity of poly (ADP-ribose) synthetase reduces ischemia-reperfusion injury in the heart and skeletal muscle. Proc Natl Acad Sci USA 1997; 94:679-683.
58. 58 Kleinman JG, Worcester EM, Beshensky AM, et al. Upregulation of osteopontin expression by ischemia in rat kidney. Ann NY Acad Sci 1995; 760:321-323.
59. 59 Hwang S, Lopez C, Heck D, et al. Osteopontin inhibits induction of nitric oxide synthase acitivity by inflammatory mediators in mouse kidney epithelial cells. J Biol Chem 1994; 269:711-715.
60. 60 Noiri E, Dickman K, Miller F, et al. Reduced tolerance to acute renal ischemia in mice with a targeted disruption of the osteopontin gene. Kidney Int 1999; 56:74-82. This study demonstrates greater susceptibility to renal ischemia-reperfusion by osteopontin knockout rats compared with wild-type controls. The knockout animals sustained greater increases in BUN and creatinine compared with wild-type rats 24 h after 30 min of ischemia. Histological changes consistent with ischemic injury were greater in the knockout animals compared with wild-type controls. NOS II protein expression was greater in knockout animals compared with wild-type controls. The osteopontin knockout animals showed greater staining for nitrotyrosine residues, suggestive of peroxynitrite production. The authors demonstrate that recombinant osteopontin protein (but not osteopontin protein lacking the RGD domain) was protective against hypoxia of cultured human proximal tubular cells in vitro.
61. 2 enzymatic activity after renal ischemia and reperfusion. J Clin Invest 1991; 87:1810-1818.
62. 2 activation in rabbit renal proximal tubules. Am J Physiol 1992; 262:F354-F360.
63. 63 Venkatachalam MA, Patel YJ, Kreisberg JI, Weinberg JM. Energy thresholds that determine membrane integrity and injury in a renal epithelial cell line (LLC-PK1). Relationship to phospholipid degradation and unesterified fatty acid accumulation. J Clin Invest 1988; 81:745-758.
64. 64 Sheridan AM, Schwartz JH, Kroshian VM, et al. Renal proximal tubular cells are more susceptible than MDCK cells to chemical anoxia. Am J Physiol 1993; 265:F342-F350.
65. 65 Kelly KJ, Tolkoff-Rubin NE, Rubin RH, et al. An oral platelet-activating factor antagonist, Ro-24-4736, protects the rat kidney from ischemic injury. Am J Physiol 1996; 271:F1061-1067.
66. 66 Lopez-Novoa JM. Potential role of platelet activating factor in acute renal failure. Kidney Int 1999; 55:1672-1682.
67. 2α stimulates proliferation, DNA synthesis endothelin-1 mRNA and protein in bovine aortic endothelial cells. Anti-endothelin antibody prevents the proliferative response.
68. 2-isoprostane formation in renal tubular cells and rat kidney. Kidney Int 1999; 55:1759-1762. Extended cold ischemia time is associated with profound vasoconstriction. There are increased isoprostanes (5X) in LLC-PK1 cells after 24 h of cold storage in University of Wisconsin solution. Cold storage of rat kidneys perfused with University of Wisconsin solution similarly increased isoprostanes. This effect was diminished with desferrioxamine and 2-methyl aminochroman (both of which inhibit lipid peroxidation).
69. 2 superfamily of signal transduction enzymes. Trends Biochem Sci 1997; 22:1-2.
70. 4 pathway to inflammation control. Nature 1996; 384:39-43.
71. 2, and a description of studies examining the potentially protective role of PPARα in ischemic reperfusion injury.
72. 72 Portilla D. Carnitine palmitoyltransferase enzyme inhibition protects proximal tubules during hypoxia. Kidney Int 1997; 52:429-437.
73. 73 Safirstein R. Renal regeneration: reiterating a developmental paradigm. Kidney Int 1999; 56:1599-1600.
74. 74 Abbate M, Brown D, Bonventre JV. Expression of NCAM recapitulates tubulogenic development in kidneys recovering from acute ischemia. Am J Physiol 1999; 277:F454-F463.
75. 75 Safirstein R, Price PM, Saggi SJ, Harris RC. Changes in gene expression after temporary renal ischemia. Kidney Int 1990; 37:1515-1521.
76. 76 Kosecki C, Herzlinger D, Al-Awqati Q. Apoptosis in metanephric development. J Cell Biol 1992; 119:1327-1333.
77. 77 Shimizu A, Yamanaka N. Apoptosis and cell desquamation in repair process of ischemic tubular necrosis. Virchows Arch B Cell Pathol 1993; 64:171-180.
78. 78 Bacallo R, Fine LG. Molecular events in the organization of renal tubular epithelium: from nephrogenesis to regeneration. Am J Physiol 1989; 257:F913-F924.
79. 79 Wallin A, Zhang G, Jones TW, et al. Mechanism of nephrogeneic repair response: studies on proliferation and vimentin expression after 32S-1,2-dichlorovinyl-L-cysteine nephrotoxicity in vivo and in cultured proximal tubule epithelial cells. Lab Invest 1992; 66:474-484.
80. 80 Witzgall R, Brown D, Schwartz C, Bonventre JV. Localization of proliferating cell nuclear antigen, vimentin c-fos and clusterin in the post-ischemic kidney. Evidence for a heterogeneous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells. J Clin Invest 1994; 93:2175-2188.
81. 81 Soifer NE, Van Why SK, Ganz MB, et al. Expression of parathyroid hormone-related protein in the rat glomerulus and tubule during recovery from renal ischemia. J Clin Invest 1993; 92:2850-2857.
82. 82 Garcia-Ocana A, Galbraith SC, Van Why SK, et al. Expression and role of parathyroid hormone-related protein in human renal proximal tubule cells during recovery from ATP depletion. J Am Soc Nephrol 1999; 10:238-244.
83. 83 Witzgall R, O'Leary E, Gessner R, et al. Kid-1, a putative renal transcription factor: regulation during ontogeny and in response to ischemia and toxic injury. Mol Cell Biol 1993; 13:1933-1942.
84. 84 Imgrund M, Grone E, Grone H, et al. Re-expression of the developmental gene Pax-2 during experimental acute tubular necrosis in mice. Kidney Int 1999; 56:1423-1431.
85. 85 Schumer M, Colombel MC, Sawczuk IS, et al. Morphologic, biochemical and molecular evidence of apoptosis during the reperfusion phase and after brief periods of renal ischemia. Am J Pathol 1992; 140:831-838.
86. 86 Lieberthal W, Menza SA, Levine JS. Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells. Am J Physiol 1998; 274:F325-F327.
87. 87 Lieberthal W, Levine J. Mechanisms of apoptosis and its potential role in renal tubular epithelial injury. Am J Physiol 1996; 271:F477-F488.
88. 88 Lieberthal W, Triaca V, Levine JS. Mechanisms of cell death induced by cisplatin in proximal tubular epithelial cells: apoptosis versus necrosis. Am J Physiol 1996; 270:F700-F708.
89. 89 Beeri R, Symon Z, Brezis M, et al. Rapid DNA fragmentation from hypoxia along the thick ascending limb of rat kidneys. Kidney Int 1995; 47:1806-1810.
90. 90 Oberbauer R, Rohrmoser M, Regele H, et al. Apoptosis of tubular epithelial cells in donor kidney biopsies predicts early renal allograft function. J Am Soc Nephrol 1999; 10:2006-2013. One of the most common early complications of transplantation is ARF. Over the past decade morphological studies have suggested the presence of apoptosis as well as necrosis. This study demonstrates increased apoptosis by TUNEL in donor biopsies of patients with biopsy proved ATN compared with those with immediate graft function. There was a significantly greater amount of apoptosis in the distal tubule, which is consistent with the morphology reported previously.
91. 91 Price PM, Megyesi J, Saggi S, Safirstein RL. Regulation of transcription by the rat EGF gene promoter in normal and ischemic murine kidney cells. Am J Physiol 1995; 268:F664-F670.
92. 92 Pombo CM, Bonventre JV, Avruch J, et al. The stress-activated protein kinases are major c-Jun amino-terminal kinases activated by ischemia and reperfusion. J Biol Chem 1994; 269:26546-26551.
93. 93 di Mari JF, Davis R, Safirstein RL. MAPK activation determines renal epithelial cell survival during oxidative injury. Am J Physiol 1999; 277:F195-F203.
94. 94 Bonventre JV, Brezis M, Siegel N, et al. Acute renal failure. I. Relative importance of proximal vs. distal tubular injury. Am J Physiol 1999; 275:F623-F632.
95. 95 Molitoris B, Weinberg JM, Venkatachalam MA, et al. Acute renal failure. II. Experimental models of acute renal failure: imperfect but indispensable. Am J Physiol 2000; 278:F1-F12. The authors discuss the strengths and limitations of models of acute renal failure.