Skip to main content
NCBI home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1997 Nov;151(5):1241–1247.

Time course and localization of endothelin-1 gene expression in a model of renal disease progression.

I Bruzzi 1, D Corna 1, C Zoja 1, S Orisio 1, E L Schiffrin 1, D Cavallotti 1, G Remuzzi 1, A Benigni 1
PMCID: PMC1858100  PMID: 9358749

Abstract

Experimental and human proteinuric glomerulopathies are associated with tubulo-interstitial injury that correlates with the decline of renal function even better than glomerular lesions do. Mechanism(s) leading to tubulo-interstitial damage are unknown. It has been proposed that excessive reabsorption of filtered proteins activates renal cells to produce vasoactive and inflammatory molecules including endothelin-1. The aim of the present study was twofold: we first evaluated the cellular origin of excessive renal endothelin-1 production in the renal mass reduction model and then related endothelin-1 distribution to the development of kidney lesions. Four groups of renal mass reduction (n = 15) and four groups of control rats (n = 5) were studied at 7, 14, 21, and 28 days after surgery. Urinary proteins in renal mass reduction rats were comparable with controls at day 7 but became significantly higher thereafter. Renal mass reduction rats first developed tubulo-interstitial changes, which were already evident at day 14 in the majority of them. At 28 days, renal mass reduction rats also developed glomerulosclerosis. A parallel increase of renal endothelin-1 gene expression and synthesis of the corresponding peptide in renal mass reduction rats versus controls was observed from day 14. Nonradioactive in situ hybridization confirmed a pattern of endothelin-1 mRNA consistent with the distribution of lesions. At day 14, endothelin-1 staining was stronger in renal mass reduction than in control kidneys and mainly localized to the cytoplasm of tubular cells, whereas glomeruli were negative. At day 28, endothelin-1 expression further increased in renal mass reduction rats as compared with controls, and the staining was apparent also in glomeruli. Thus, in renal mass reduction, a progressive up-regulation of endothelin-1 occurs during the development of renal injury, that first involves the tubules and, only in a subsequent phase, the glomeruli.

Full text

PDF
1241

Images in this article

1245Figure 2
on p.1245

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Achmad T. H., Rao G. S. Chemotaxis of human blood monocytes toward endothelin-1 and the influence of calcium channel blockers. Biochem Biophys Res Commun. 1992 Dec 15;189(2):994–1000. doi: 10.1016/0006-291x(92)92302-e. [DOI] [PubMed] [Google Scholar]
  2. Aiello S., Noris M., Todeschini M., Zappella S., Foglieni C., Benigni A., Corna D., Zoja C., Cavallotti D., Remuzzi G. Renal and systemic nitric oxide synthesis in rats with renal mass reduction. Kidney Int. 1997 Jul;52(1):171–181. doi: 10.1038/ki.1997.317. [DOI] [PubMed] [Google Scholar]
  3. Anderson S., Meyer T. W., Rennke H. G., Brenner B. M. Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest. 1985 Aug;76(2):612–619. doi: 10.1172/JCI112013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Anderson S., Rennke H. G., Brenner B. M. Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest. 1986 Jun;77(6):1993–2000. doi: 10.1172/JCI112528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ashab I., Peer G., Blum M., Wollman Y., Chernihovsky T., Hassner A., Schwartz D., Cabili S., Silverberg D., Iaina A. Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production. Kidney Int. 1995 Jun;47(6):1515–1521. doi: 10.1038/ki.1995.214. [DOI] [PubMed] [Google Scholar]
  6. Benigni A., Zoja C., Corna D., Orisio S., Longaretti L., Bertani T., Remuzzi G. A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int. 1993 Aug;44(2):440–444. doi: 10.1038/ki.1993.263. [DOI] [PubMed] [Google Scholar]
  7. Benigni A., Zola C., Corna D., Orisio S., Facchinetti D., Benati L., Remuzzi G. Blocking both type A and B endothelin receptors in the kidney attenuates renal injury and prolongs survival in rats with remnant kidney. Am J Kidney Dis. 1996 Mar;27(3):416–423. doi: 10.1016/s0272-6386(96)90366-2. [DOI] [PubMed] [Google Scholar]
  8. Bohle A., Wehrmann M., Bogenschütz O., Batz C., Müller C. A., Müller G. A. The pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of 488 cases of diabetic glomerulosclerosis. Pathol Res Pract. 1991 Mar;187(2-3):251–259. doi: 10.1016/s0344-0338(11)80780-6. [DOI] [PubMed] [Google Scholar]
  9. Diamond J. R., Anderson S. Irreversible tubulointerstitial damage associated with chronic aminonucleoside nephrosis. Amelioration by angiotensin I converting enzyme inhibition. Am J Pathol. 1990 Dec;137(6):1323–1332. [PMC free article] [PubMed] [Google Scholar]
  10. Eddy A. A. Interstitial nephritis induced by protein-overload proteinuria. Am J Pathol. 1989 Oct;135(4):719–733. [PMC free article] [PubMed] [Google Scholar]
  11. Floege J., Burns M. W., Alpers C. E., Yoshimura A., Pritzl P., Gordon K., Seifert R. A., Bowen-Pope D. F., Couser W. G., Johnson R. J. Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney Int. 1992 Feb;41(2):297–309. doi: 10.1038/ki.1992.42. [DOI] [PubMed] [Google Scholar]
  12. Ingram A., Parbtani A., Thai K., Ly H., Shankland S. J., Morrissey G., Scholey J. W. Dietary supplementation with L-arginine limits cell proliferation in the remnant glomerulus. Kidney Int. 1995 Dec;48(6):1857–1865. doi: 10.1038/ki.1995.484. [DOI] [PubMed] [Google Scholar]
  13. Iwasaki S., Homma T., Matsuda Y., Kon V. Endothelin receptor subtype B mediates autoinduction of endothelin-1 in rat mesangial cells. J Biol Chem. 1995 Mar 24;270(12):6997–7003. doi: 10.1074/jbc.270.12.6997. [DOI] [PubMed] [Google Scholar]
  14. Kasinath B. S., Fried T. A., Davalath S., Marsden P. A. Glomerular epithelial cells synthesize endothelin peptides. Am J Pathol. 1992 Aug;141(2):279–283. [PMC free article] [PubMed] [Google Scholar]
  15. Kohan D. E., Padilla E. Endothelin-1 is an autocrine factor in rat inner medullary collecting ducts. Am J Physiol. 1992 Oct;263(4 Pt 2):F607–F612. doi: 10.1152/ajprenal.1992.263.4.F607. [DOI] [PubMed] [Google Scholar]
  16. Kourembanas S., McQuillan L. P., Leung G. K., Faller D. V. Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest. 1993 Jul;92(1):99–104. doi: 10.1172/JCI116604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lee L. K., Meyer T. W., Pollock A. S., Lovett D. H. Endothelial cell injury initiates glomerular sclerosis in the rat remnant kidney. J Clin Invest. 1995 Aug;96(2):953–964. doi: 10.1172/JCI118143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mackensen-Haen S., Eissele R., Bohle A. Contribution on the correlation between morphometric parameters gained from the renal cortex and renal function in IgA nephritis. Lab Invest. 1988 Aug;59(2):239–244. [PubMed] [Google Scholar]
  19. Marsden P. A., Dorfman D. M., Collins T., Brenner B. M., Orkin S. H., Ballermann B. J. Regulated expression of endothelin 1 in glomerular capillary endothelial cells. Am J Physiol. 1991 Jul;261(1 Pt 2):F117–F125. doi: 10.1152/ajprenal.1991.261.1.F117. [DOI] [PubMed] [Google Scholar]
  20. Mori H., Yamashita H., Nakanishi C., Koizumi K., Makino S., Kishimoto Y., Hayashi Y. Proteinuria induced by transplantable rat pituitary tumor MtT SA5. Model for homologous protein-overload proteinuria. Lab Invest. 1986 Jun;54(6):636–644. [PubMed] [Google Scholar]
  21. Morrissey J. J., Ishidoya S., McCracken R., Klahr S. Nitric oxide generation ameliorates the tubulointerstitial fibrosis of obstructive nephropathy. J Am Soc Nephrol. 1996 Oct;7(10):2202–2212. doi: 10.1681/ASN.V7102202. [DOI] [PubMed] [Google Scholar]
  22. Nakamura T., Ebihara I., Tomino Y., Koide H. Effect of a specific endothelin A receptor antagonist on murine lupus nephritis. Kidney Int. 1995 Feb;47(2):481–489. doi: 10.1038/ki.1995.61. [DOI] [PubMed] [Google Scholar]
  23. O'Dell J. R., Hays R. C., Guggenheim S. J., Steigerwald J. C. Tubulointerstitial renal disease in systemic lupus erythematosus. Arch Intern Med. 1985 Nov;145(11):1996–1999. [PubMed] [Google Scholar]
  24. Olson J. L. Role of heparin as a protective agent following reduction of renal mass. Kidney Int. 1984 Feb;25(2):376–382. doi: 10.1038/ki.1984.27. [DOI] [PubMed] [Google Scholar]
  25. Ong A. C., Jowett T. P., Firth J. D., Burton S., Karet F. E., Fine L. G. An endothelin-1 mediated autocrine growth loop involved in human renal tubular regeneration. Kidney Int. 1995 Aug;48(2):390–401. doi: 10.1038/ki.1995.307. [DOI] [PubMed] [Google Scholar]
  26. Orisio S., Benigni A., Bruzzi I., Corna D., Perico N., Zoja C., Benatti L., Remuzzi G. Renal endothelin gene expression is increased in remnant kidney and correlates with disease progression. Kidney Int. 1993 Feb;43(2):354–358. doi: 10.1038/ki.1993.53. [DOI] [PubMed] [Google Scholar]
  27. Pupilli C., Brunori M., Misciglia N., Selli C., Ianni L., Yanagisawa M., Mannelli M., Serio M. Presence and distribution of endothelin-1 gene expression in human kidney. Am J Physiol. 1994 Oct;267(4 Pt 2):F679–F687. doi: 10.1152/ajprenal.1994.267.4.F679. [DOI] [PubMed] [Google Scholar]
  28. Read S. M., Northcote D. H. Minimization of variation in the response to different proteins of the Coomassie blue G dye-binding assay for protein. Anal Biochem. 1981 Sep 1;116(1):53–64. doi: 10.1016/0003-2697(81)90321-3. [DOI] [PubMed] [Google Scholar]
  29. Remuzzi G. Abnormal protein traffic through the glomerular barrier induces proximal tubular cell dysfunction and causes renal injury. Curr Opin Nephrol Hypertens. 1995 Jul;4(4):339–342. doi: 10.1097/00041552-199507000-00009. [DOI] [PubMed] [Google Scholar]
  30. Remuzzi G., Bertani T. Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules? Kidney Int. 1990 Sep;38(3):384–394. doi: 10.1038/ki.1990.217. [DOI] [PubMed] [Google Scholar]
  31. Saijonmaa O., Nyman T., Fyhrquist F. Endothelin-1 stimulates its own synthesis in human endothelial cells. Biochem Biophys Res Commun. 1992 Oct 15;188(1):286–291. doi: 10.1016/0006-291x(92)92382-8. [DOI] [PubMed] [Google Scholar]
  32. Sakamoto H., Sasaki S., Nakamura Y., Fushimi K., Marumo F. Regulation of endothelin-1 production in cultured rat mesangial cells. Kidney Int. 1992 Feb;41(2):350–355. doi: 10.1038/ki.1992.48. [DOI] [PubMed] [Google Scholar]
  33. Schmitt H., Cavalcanti de Oliveira V., Bohle A. Tubulo-interstitial alterations in type I membranoproliferative glomerulonephritis. An investigation of 259 cases. Pathol Res Pract. 1987 Feb;182(1):6–10. doi: 10.1016/S0344-0338(87)80136-X. [DOI] [PubMed] [Google Scholar]
  34. Silldorff E. P., Yang S., Pallone T. L. Prostaglandin E2 abrogates endothelin-induced vasoconstriction in renal outer medullary descending vasa recta of the rat. J Clin Invest. 1995 Jun;95(6):2734–2740. doi: 10.1172/JCI117976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wehrmann M., Bohle A., Held H., Schumm G., Kendziorra H., Pressler H. Long-term prognosis of focal sclerosing glomerulonephritis. An analysis of 250 cases with particular regard to tubulointerstitial changes. Clin Nephrol. 1990 Mar;33(3):115–122. [PubMed] [Google Scholar]
  36. Wilkes B. M., Susin M., Mento P. F., Macica C. M., Girardi E. P., Boss E., Nord E. P. Localization of endothelin-like immunoreactivity in rat kidneys. Am J Physiol. 1991 Jun;260(6 Pt 2):F913–F920. doi: 10.1152/ajprenal.1991.260.6.F913. [DOI] [PubMed] [Google Scholar]
  37. Zoja C., Corna D., Bruzzi I., Foglieni C., Bertani T., Remuzzi G., Benigni A. Passive Heymann nephritis: evidence that angiotensin-converting enzyme inhibition reduces proteinuria and retards renal structural injury. Exp Nephrol. 1996 Jul-Aug;4(4):213–221. [PubMed] [Google Scholar]
  38. Zoja C., Morigi M., Figliuzzi M., Bruzzi I., Oldroyd S., Benigni A., Ronco P., Remuzzi G. Proximal tubular cell synthesis and secretion of endothelin-1 on challenge with albumin and other proteins. Am J Kidney Dis. 1995 Dec;26(6):934–941. doi: 10.1016/0272-6386(95)90058-6. [DOI] [PubMed] [Google Scholar]
  39. Zoja C., Orisio S., Perico N., Benigni A., Morigi M., Benatti L., Rambaldi A., Remuzzi G. Constitutive expression of endothelin gene in cultured human mesangial cells and its modulation by transforming growth factor-beta, thrombin, and a thromboxane A2 analogue. Lab Invest. 1991 Jan;64(1):16–20. [PubMed] [Google Scholar]
  40. Zoja C., Remuzzi A., Corna D., Perico N., Bertani T., Remuzzi G. Renal protective effect of angiotensin-converting enzyme inhibition in aging rats. Am J Med. 1992 Apr 27;92(4B):60S–63S. doi: 10.1016/0002-9343(92)90149-6. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES