Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension (original) (raw)

Abstract

The human endothelin-1 (ET-1) gene under the control of its natural promoter was transferred into the germline of mice. The transgene was expressed predominantly in the brain, lung, and kidney. Transgene expression was associated with a pathological phenotype manifested by signs such as age-dependent development of renal cysts, interstitial fibrosis of the kidneys, and glomerulosclerosis leading to a progressive decrease in glomerular filtration rate. This pathology developed in spite of only slightly elevated plasma and tissue ET-1 concentrations. Blood pressure was not affected even after the development of an impaired glomerular filtration rate. Therefore, these transgenic lines provide a new blood pressure-independent animal model of ET-1-induced renal pathology leading to renal fibrosis and fatal kidney disease.

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Selected References

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  1. Bazil M. K., Lappe R. W., Webb R. L. Pharmacologic characterization of an endothelinA (ETA) receptor antagonist in conscious rats. J Cardiovasc Pharmacol. 1992 Dec;20(6):940–948. doi: 10.1097/00005344-199212000-00014. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Bloch K. D., Friedrich S. P., Lee M. E., Eddy R. L., Shows T. B., Quertermous T. Structural organization and chromosomal assignment of the gene encoding endothelin. J Biol Chem. 1989 Jun 25;264(18):10851–10857. [PubMed] [Google Scholar]
  4. Carone F. A., Bacallao R., Kanwar Y. S. The pathogenesis of polycystic kidney disease. Histol Histopathol. 1995 Jan;10(1):213–221. [PubMed] [Google Scholar]
  5. Carone F. A., Butkowski R. J., Nakamura S., Polenakovic M., Kanwar Y. S. Tubular basement membrane changes during induction and regression of drug-induced polycystic kidney disease. Kidney Int. 1994 Nov;46(5):1368–1374. doi: 10.1038/ki.1994.406. [DOI] [PubMed] [Google Scholar]
  6. Gellai M., DeWolf R., Pullen M., Nambi P. Distribution and functional role of renal ET receptor subtypes in normotensive and hypertensive rats. Kidney Int. 1994 Nov;46(5):1287–1294. doi: 10.1038/ki.1994.396. [DOI] [PubMed] [Google Scholar]
  7. Hirata Y., Emori T., Eguchi S., Kanno K., Imai T., Ohta K., Marumo F. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest. 1993 Apr;91(4):1367–1373. doi: 10.1172/JCI116338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hocher B., Liefeldt L., Thöne-Reineke C., Orzechowski H. D., Distler A., Bauer C., Paul M. Characterization of the renal phenotype of transgenic rats expressing the human endothelin-2 gene. Hypertension. 1996 Aug;28(2):196–201. doi: 10.1161/01.hyp.28.2.196. [DOI] [PubMed] [Google Scholar]
  9. Hocher B., Rohmeiss P., Zart R., Diekmann F., Vogt V., Metz D., Fakhury M., Gretz N., Bauer C., Koppenhagen K. Function and expression of endothelin receptor subtypes in the kidneys of spontaneously hypertensive rats. Cardiovasc Res. 1996 Apr;31(4):499–510. [PubMed] [Google Scholar]
  10. Hocher B., Zart R., Diekmann F., Rohmeiss P., Distler A., Neumayer H. H., Bauer C., Gross P. Paracrine renal endothelin system in rats with liver cirrhosis. Br J Pharmacol. 1996 May;118(2):220–227. doi: 10.1111/j.1476-5381.1996.tb15390.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hocher B., Zart R., Diekmann F., Slowinski T., Thöne-Reineke C., Lutz J., Bauer C. Role of the paracrine liver endothelin system in the pathogenesis of CCl4-induced liver injury. Eur J Pharmacol. 1995 Dec 7;293(4):361–368. doi: 10.1016/0926-6917(95)90056-x. [DOI] [PubMed] [Google Scholar]
  12. Kohan D. E. Endothelins in the kidney: physiology and pathophysiology. Am J Kidney Dis. 1993 Oct;22(4):493–510. doi: 10.1016/s0272-6386(12)80920-6. [DOI] [PubMed] [Google Scholar]
  13. Kohan D. E., Padilla E. Endothelin-1 production by rat inner medullary collecting duct: effect of nitric oxide, cGMP, and immune cytokines. Am J Physiol. 1994 Feb;266(2 Pt 2):F291–F297. doi: 10.1152/ajprenal.1994.266.2.F291. [DOI] [PubMed] [Google Scholar]
  14. Kurihara Y., Kurihara H., Suzuki H., Kodama T., Maemura K., Nagai R., Oda H., Kuwaki T., Cao W. H., Kamada N. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature. 1994 Apr 21;368(6473):703–710. doi: 10.1038/368703a0. [DOI] [PubMed] [Google Scholar]
  15. Li J. S., Schiffrin E. L. Effect of chronic treatment of adult spontaneously hypertensive rats with an endothelin receptor antagonist. Hypertension. 1995 Apr;25(4 Pt 1):495–500. doi: 10.1161/01.hyp.25.4.495. [DOI] [PubMed] [Google Scholar]
  16. Lüscher T. F., Seo B. G., Bühler F. R. Potential role of endothelin in hypertension. Controversy on endothelin in hypertension. Hypertension. 1993 Jun;21(6 Pt 1):752–757. doi: 10.1161/01.hyp.21.6.752. [DOI] [PubMed] [Google Scholar]
  17. Moritoki H., Miyano H., Takeuchi S., Yamaguchi M., Hisayama T., Kondoh W. Endothelin-3-induced relaxation of rat thoracic aorta: a role for nitric oxide formation. Br J Pharmacol. 1993 Apr;108(4):1125–1130. doi: 10.1111/j.1476-5381.1993.tb13515.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Murer L., Zacchello G., Basso G., Scarpa A., Montini G., Chiozza M. L., Zacchello F. Immunohistochemical distribution of endothelin in biopsies of pediatric nephrotic syndrome. Am J Nephrol. 1994;14(3):157–161. doi: 10.1159/000168707. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Nassar G. M., Badr K. F. Endothelin in kidney disease. Curr Opin Nephrol Hypertens. 1994 Jan;3(1):86–91. doi: 10.1097/00041552-199401000-00012. [DOI] [PubMed] [Google Scholar]
  21. Nath K. A. Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis. 1992 Jul;20(1):1–17. doi: 10.1016/s0272-6386(12)80312-x. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. 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]
  24. Raij L., Azar S., Keane W. Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int. 1984 Aug;26(2):137–143. doi: 10.1038/ki.1984.147. [DOI] [PubMed] [Google Scholar]
  25. Risdon R. A., Sloper J. C., De Wardener H. E. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet. 1968 Aug 17;2(7564):363–366. doi: 10.1016/s0140-6736(68)90589-8. [DOI] [PubMed] [Google Scholar]
  26. Roccatello D., Mosso R., Ferro M., Polloni R., De Filippi P. G., Quattrocchio G., Bancale E., Cesano G., Sena L. M., Piccoli G. Urinary endothelin in glomerulonephritis patients with normal renal function. Clin Nephrol. 1994 Jun;41(6):323–330. [PubMed] [Google Scholar]
  27. Ruíz-Ortega M., Gómez-Garre D., Alcázar R., Palacios I., Bustos C., González S., Plaza J. J., González E., Egido J. Involvement of angiotensin II and endothelin in matrix protein production and renal sclerosis. J Hypertens Suppl. 1994 Jul;12(4):S51–S58. [PubMed] [Google Scholar]
  28. Schiffrin E. L., Larivière R., Li J. S., Sventek P., Touyz R. M. Deoxycorticosterone acetate plus salt induces overexpression of vascular endothelin-1 and severe vascular hypertrophy in spontaneously hypertensive rats. Hypertension. 1995 Apr;25(4 Pt 2):769–773. doi: 10.1161/01.hyp.25.4.769. [DOI] [PubMed] [Google Scholar]
  29. Schäfer K., Bader M., Gretz N., Oberbäumer I., Bachmann S. Focal overexpression of collagen IV characterizes the initiation of epithelial changes in polycystic kidney disease. Exp Nephrol. 1994 May-Jun;2(3):190–195. [PubMed] [Google Scholar]
  30. Sibilia M., Wagner E. F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science. 1995 Jul 14;269(5221):234–238. doi: 10.1126/science.7618085. [DOI] [PubMed] [Google Scholar]
  31. Theuring F., Götz W., Balling R., Korf H. W., Schulze F., Herken R., Gruss P. Tumorigenesis and eye abnormalities in transgenic mice expressing MSV-SV40 large T-antigen. Oncogene. 1990 Feb;5(2):225–232. [PubMed] [Google Scholar]
  32. Wehrmann M., Bohle A., Bogenschütz O., Eissele R., Freislederer A., Ohlschlegel C., Schumm G., Batz C., Gärtner H. V. Long-term prognosis of chronic idiopathic membranous glomerulonephritis. An analysis of 334 cases with particular regard to tubulo-interstitial changes. Clin Nephrol. 1989 Feb;31(2):67–76. [PubMed] [Google Scholar]
  33. Yamamoto T., Noble N. A., Miller D. E., Border W. A. Sustained expression of TGF-beta 1 underlies development of progressive kidney fibrosis. Kidney Int. 1994 Mar;45(3):916–927. doi: 10.1038/ki.1994.122. [DOI] [PubMed] [Google Scholar]