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. 1989 Dec;84(6):1757–1761. doi: 10.1172/JCI114359

Epidermal growth factor enhances renal tubule cell regeneration and repair and accelerates the recovery of renal function in postischemic acute renal failure.

H D Humes 1, D A Cieslinski 1, T M Coimbra 1, J M Messana 1, C Galvao 1
PMCID: PMC304052  PMID: 2592559

Abstract

To determine the timing and location of renal cell regeneration after ischemic injury to the kidney and to assess whether exogenous epidermal growth factor (EGF) enhances this regenerative repair process to accelerate recovery of renal function, experiments were undertaken in rats undergoing 30 min of bilateral renal artery clamp ischemia followed by reperfusion for varying time intervals. Renal cell regeneration, as reflected by incorporation of radiolabeled thymidine within the kidney, began between 24 to 48 h and reached a peak at 72 h after renal ischemia. As demonstrated by histoautoradiography, renal thymidine incorporation was essentially confined to tubule cells. Morphometric analysis of histoautoradiograph sections of renal tissue demonstrated that the majority of labeled cells were found in renal cortex, but some labeled cells were also located in the inner stripe of the outer medulla, suggesting that injury to medullary thick ascending limbs also occurs in this ischemic model. Exogenous EGF administration produced increases in renal thymidine incorporation compared with non-treated animals at 24, 48, and 72 h after ischemic injury. This accelerated DNA replicative process was associated with significantly lower peak blood urea nitrogen (BUN) and serum creatinine levels, averaging 63 +/- 20 and 3.1 +/- 0.4 mg/dl in EGF-treated ischemic rats compared with 149 +/- 20 and 5.1 +/- 0.1 mg/dl, respectively, in nontreated ischemic rats, and was also associated with a return to near normal BUN and serum creatinine levels in EGF-treated animals approximately 4 d earlier than that observed in nontreated animals. This report is the first demonstration that EGF accelerates the repair process of a visceral organ after an injurious insult.

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Selected References

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  1. Assoian R. K., Grotendorst G. R., Miller D. M., Sporn M. B. Cellular transformation by coordinated action of three peptide growth factors from human platelets. 1984 Jun 28-Jul 4Nature. 309(5971):804–806. doi: 10.1038/309804a0. [DOI] [PubMed] [Google Scholar]
  2. Bell G. I., Fong N. M., Stempien M. M., Wormsted M. A., Caput D., Ku L. L., Urdea M. S., Rall L. B., Sanchez-Pescador R. Human epidermal growth factor precursor: cDNA sequence, expression in vitro and gene organization. Nucleic Acids Res. 1986 Nov 11;14(21):8427–8446. doi: 10.1093/nar/14.21.8427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Breyer M. D., Jacobson H. R., Breyer J. A. Epidermal growth factor inhibits the hydroosmotic effect of vasopressin in the isolated perfused rabbit cortical collecting tubule. J Clin Invest. 1988 Oct;82(4):1313–1320. doi: 10.1172/JCI113732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brezis M., Rosen S., Silva P., Epstein F. H. Renal ischemia: a new perspective. Kidney Int. 1984 Oct;26(4):375–383. doi: 10.1038/ki.1984.185. [DOI] [PubMed] [Google Scholar]
  5. Brezis M., Rosen S., Silva P., Epstein F. H. Selective vulnerability of the medullary thick ascending limb to anoxia in the isolated perfused rat kidney. J Clin Invest. 1984 Jan;73(1):182–190. doi: 10.1172/JCI111189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brightwell J. R., Riddle S. L., Eiferman R. A., Valenzuela P., Barr P. J., Merryweather J. P., Schultz G. S. Biosynthetic human EGF accelerates healing of Neodecadron-treated primate corneas. Invest Ophthalmol Vis Sci. 1985 Jan;26(1):105–110. [PubMed] [Google Scholar]
  7. Brown G. L., Curtsinger L., 3rd, Brightwell J. R., Ackerman D. M., Tobin G. R., Polk H. C., Jr, George-Nascimento C., Valenzuela P., Schultz G. S. Enhancement of epidermal regeneration by biosynthetic epidermal growth factor. J Exp Med. 1986 May 1;163(5):1319–1324. doi: 10.1084/jem.163.5.1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cuppage F. E., Chiga M., Tate A. Cell cycle studies in the regenerating rat nephron following injury with mercuric chloride. Lab Invest. 1972 Jan;26(1):122–126. [PubMed] [Google Scholar]
  9. Derynck R. Transforming growth factor alpha. Cell. 1988 Aug 26;54(5):593–595. doi: 10.1016/s0092-8674(88)80001-1. [DOI] [PubMed] [Google Scholar]
  10. Donohoe J. F., Venkatachalam M. A., Bernard D. B., Levinsky N. G. Tubular leakage and obstruction after renal ischemia: structural-functional correlations. Kidney Int. 1978 Mar;13(3):208–222. doi: 10.1038/ki.1978.31. [DOI] [PubMed] [Google Scholar]
  11. Gregory H. Isolation and structure of urogastrone and its relationship to epidermal growth factor. Nature. 1975 Sep 25;257(5524):325–327. doi: 10.1038/257325a0. [DOI] [PubMed] [Google Scholar]
  12. Harris R. C., Hoover R. L., Jacobson H. R., Badr K. F. Evidence for glomerular actions of epidermal growth factor in the rat. J Clin Invest. 1988 Sep;82(3):1028–1039. doi: 10.1172/JCI113659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Heyman S. N., Brezis M., Reubinoff C. A., Greenfeld Z., Lechene C., Epstein F. H., Rosen S. Acute renal failure with selective medullary injury in the rat. J Clin Invest. 1988 Aug;82(2):401–412. doi: 10.1172/JCI113612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Humes H. D., Weinberg J. M. Alterations of renal tubular cell metabolism in acute renal failure. Miner Electrolyte Metab. 1983;9(4-6):290–305. [PubMed] [Google Scholar]
  15. Imada O., Hayashi N., Masamoto K., Kasuga S., Fuwa T., Nakagawa S. Long-latency growth-promoting activity of EGF when administered to mice at the neonatal stage. Am J Physiol. 1987 Sep;253(3 Pt 1):E251–E254. doi: 10.1152/ajpendo.1987.253.3.E251. [DOI] [PubMed] [Google Scholar]
  16. Jackson N. M., Hsu C. H., Visscher G. E., Venkatachalam M. A., Humes H. D. Alterations in renal structure and function in a rat model of cyclosporine nephrotoxicity. J Pharmacol Exp Ther. 1987 Aug;242(2):749–756. [PubMed] [Google Scholar]
  17. Kreisberg J. I., Bulger R. E., Trump B. F., Nagle R. B. Effects of transient hypotension on the structure and function of rat kidney. Virchows Arch B Cell Pathol. 1976 Nov 2;22(2):121–133. doi: 10.1007/BF02889210. [DOI] [PubMed] [Google Scholar]
  18. Laurent G., Maldague P., Carlier M. B., Tulkens P. M. Increased renal DNA synthesis in vivo after administration of low doses of gentamicin to rats. Antimicrob Agents Chemother. 1983 Oct;24(4):586–593. doi: 10.1128/aac.24.4.586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Moran S. M., Myers B. D. Pathophysiology of protracted acute renal failure in man. J Clin Invest. 1985 Oct;76(4):1440–1448. doi: 10.1172/JCI112122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Niall M., Ryan G. B., O'Brien B. M. The effect of epidermal growth factor on wound healing in mice. J Surg Res. 1982 Aug;33(2):164–169. doi: 10.1016/0022-4804(82)90024-5. [DOI] [PubMed] [Google Scholar]
  21. Norman J., Badie-Dezfooly B., Nord E. P., Kurtz I., Schlosser J., Chaudhari A., Fine L. G. EGF-induced mitogenesis in proximal tubular cells: potentiation by angiotensin II. Am J Physiol. 1987 Aug;253(2 Pt 2):F299–F309. doi: 10.1152/ajprenal.1987.253.2.F299. [DOI] [PubMed] [Google Scholar]
  22. Oka Y., Orth D. N. Human plasma epidermal growth factor/beta-urogastrone is associated with blood platelets. J Clin Invest. 1983 Jul;72(1):249–259. doi: 10.1172/JCI110964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rall L. B., Scott J., Bell G. I., Crawford R. J., Penschow J. D., Niall H. D., Coghlan J. P. Mouse prepro-epidermal growth factor synthesis by the kidney and other tissues. Nature. 1985 Jan 17;313(5999):228–231. doi: 10.1038/313228a0. [DOI] [PubMed] [Google Scholar]
  24. SWANN R. C., MERRILL J. P. The clinical course of acute renal failure. Medicine (Baltimore) 1953 May;32(2):215–292. doi: 10.1097/00005792-195305000-00002. [DOI] [PubMed] [Google Scholar]
  25. Schultz G. S., White M., Mitchell R., Brown G., Lynch J., Twardzik D. R., Todaro G. J. Epithelial wound healing enhanced by transforming growth factor-alpha and vaccinia growth factor. Science. 1987 Jan 16;235(4786):350–352. doi: 10.1126/science.3492044. [DOI] [PubMed] [Google Scholar]
  26. Skov Olsen P., Nexø E., Poulsen S. S., Hansen H. F., Kirkegaard P. Renal origin of rat urinary epidermal growth factor. Regul Pept. 1984 Dec;10(1):37–45. doi: 10.1016/0167-0115(84)90051-x. [DOI] [PubMed] [Google Scholar]
  27. Tashjian A. H., Jr, Voelkel E. F., Lloyd W., Derynck R., Winkler M. E., Levine L. Actions of growth factors on plasma calcium. Epidermal growth factor and human transforming growth factor-alpha cause elevation of plasma calcium in mice. J Clin Invest. 1986 Nov;78(5):1405–1409. doi: 10.1172/JCI112728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Venkatachalam M. A., Bernard D. B., Donohoe J. F., Levinsky N. G. Ischemic damage and repair in the rat proximal tubule: differences among the S1, S2, and S3 segments. Kidney Int. 1978 Jul;14(1):31–49. doi: 10.1038/ki.1978.87. [DOI] [PubMed] [Google Scholar]
  29. Wilson P. D., Schrier R. W. Nephron segment and calcium as determinants of anoxic cell death in renal cultures. Kidney Int. 1986 Jun;29(6):1172–1179. doi: 10.1038/ki.1986.124. [DOI] [PubMed] [Google Scholar]
  30. Woost P. G., Brightwell J., Eiferman R. A., Schultz G. S. Effect of growth factors with dexamethasone on healing of rabbit corneal stromal incisions. Exp Eye Res. 1985 Jan;40(1):47–60. doi: 10.1016/0014-4835(85)90107-1. [DOI] [PubMed] [Google Scholar]

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