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J Clin Invest. Mar 15, 1997; 99(6): 1380–1389.
PMCID: PMC507954

Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension.

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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  • Kohan DE. Endothelins in the kidney: physiology and pathophysiology. Am J Kidney Dis. 1993 Oct;22(4):493–510. [PubMed]
  • Hocher B, Zart R, Diekmann F, Rohmeiss P, Distler A, Neumayer HH, Bauer C, Gross P. Paracrine renal endothelin system in rats with liver cirrhosis. Br J Pharmacol. 1996 May;118(2):220–227. [PMC free article] [PubMed]
  • Lüscher TF, Seo BG, Bühler FR. Potential role of endothelin in hypertension. Controversy on endothelin in hypertension. Hypertension. 1993 Jun;21(6 Pt 1):752–757. [PubMed]
  • Hocher B, Rohmeiss P, Zart R, Diekmann F, Vogt V, Metz D, Fakhury M, Gretz N, Bauer C, Koppenhagen K, et al. Function and expression of endothelin receptor subtypes in the kidneys of spontaneously hypertensive rats. Cardiovasc Res. 1996 Apr;31(4):499–510. [PubMed]
  • Ruíz-Ortega M, Gómez-Garre D, Alcázar R, Palacios I, Bustos C, González S, Plaza JJ, 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]
  • Murer L, Zacchello G, Basso G, Scarpa A, Montini G, Chiozza ML, Zacchello F. Immunohistochemical distribution of endothelin in biopsies of pediatric nephrotic syndrome. Am J Nephrol. 1994;14(3):157–161. [PubMed]
  • 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. [PubMed]
  • Roccatello D, Mosso R, Ferro M, Polloni R, De Filippi PG, Quattrocchio G, Bancale E, Cesano G, Sena LM, Piccoli G. Urinary endothelin in glomerulonephritis patients with normal renal function. Clin Nephrol. 1994 Jun;41(6):323–330. [PubMed]
  • Bloch KD, Friedrich SP, Lee ME, Eddy RL, Shows TB, Quertermous T. Structural organization and chromosomal assignment of the gene encoding endothelin. J Biol Chem. 1989 Jun 25;264(18):10851–10857. [PubMed]
  • Theuring F, Götz W, Balling R, Korf HW, 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]
  • 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. [PubMed]
  • 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. [PubMed]
  • Yamamoto T, Noble NA, Miller DE, Border WA. Sustained expression of TGF-beta 1 underlies development of progressive kidney fibrosis. Kidney Int. 1994 Mar;45(3):916–927. [PubMed]
  • Schiffrin EL, Larivière R, Li JS, Sventek P, Touyz RM. 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. [PubMed]
  • 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. [PubMed]
  • Bazil MK, Lappe RW, Webb RL. Pharmacologic characterization of an endothelinA (ETA) receptor antagonist in conscious rats. J Cardiovasc Pharmacol. 1992 Dec;20(6):940–948. [PubMed]
  • Li JS, Schiffrin EL. Effect of chronic treatment of adult spontaneously hypertensive rats with an endothelin receptor antagonist. Hypertension. 1995 Apr;25(4 Pt 1):495–500. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Kohan DE, 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. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Kurihara Y, Kurihara H, Suzuki H, Kodama T, Maemura K, Nagai R, Oda H, Kuwaki T, Cao WH, Kamada N, et al. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature. 1994 Apr 21;368(6473):703–710. [PubMed]
  • Sibilia M, Wagner EF. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science. 1995 Jul 14;269(5221):234–238. [PubMed]
  • 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]
  • Carone FA, Butkowski RJ, Nakamura S, Polenakovic M, Kanwar YS. Tubular basement membrane changes during induction and regression of drug-induced polycystic kidney disease. Kidney Int. 1994 Nov;46(5):1368–1374. [PubMed]
  • Carone FA, Bacallao R, Kanwar YS. The pathogenesis of polycystic kidney disease. Histol Histopathol. 1995 Jan;10(1):213–221. [PubMed]
  • 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. [PubMed]
  • 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. [PubMed]
  • Hocher B, Liefeldt L, Thöne-Reineke C, Orzechowski HD, 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. [PubMed]
  • Nath KA. Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis. 1992 Jul;20(1):1–17. [PubMed]
  • Risdon RA, Sloper JC, De Wardener HE. 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. [PubMed]
  • Wehrmann M, Bohle A, Bogenschütz O, Eissele R, Freislederer A, Ohlschlegel C, Schumm G, Batz C, Gärtner HV. 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]
  • Nassar GM, Badr KF. Endothelin in kidney disease. Curr Opin Nephrol Hypertens. 1994 Jan;3(1):86–91. [PubMed]
  • Ong AC, Jowett TP, Firth JD, Burton S, Karet FE, Fine LG. An endothelin-1 mediated autocrine growth loop involved in human renal tubular regeneration. Kidney Int. 1995 Aug;48(2):390–401. [PubMed]

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