Abstract
The kidney is an important site of endothelin‐1 (ET‐1) production and is particularly susceptible to ET‐1 action. Infusion of ET‐1 in rats induces both functional and morphological alterations in the kidneys. Increased plasma level of ET‐1 has been reported in patients with chronic renal failure. However, there are still no reports on the plasma and urinary ET‐1 levels in patients with focal segmental glomerulosclerosis (FSGS). In the present study, we have measured the plasma concentration and urinary excretion rate of ET‐1 in 15 patients with nephrotic syndrome due to FSGS, and observed the serial changes of plasma and urinary ET‐1 in nephrotic rats with FSGS, induced by repeated injection with puromycin aminonucleoside (PAN). ET‐1 was measured with radioimmunoassay. The results showed that plasma ET‐1 concentration in FSGS patients was significantly higher than in normal controls (P < 0.05), and that urinary ET‐1 excretion rate was also significantly higher in FSGS patients than in normal controls (P < 0.01). In FSGS patients, the plasma and urinary ET‐1 was significantly correlated (P < 0.05), and the urinary ET‐1 excretion rate was significantly correlated with the amount of proteinuria (P < 0.05) and the glomerular sclerosing score (P < 0.01). In the ten rats with PAN‐induced FSGS, serial examination showed a significant increase in plasma ET‐1 after 8 weeks of injections, while the urinary ET‐1 excretion rate showed a biphasic increase that showed a peak after 4 to 6 weeks. The same changes in plasma and urinary ET‐1 levels were not observed in control rats injected with normal saline at the same frequency. Our results suggest that ET‐1 may be involved in the pathogenesis of FSGS in both humans and rats. J. Clin. Lab. Anal. 15:59–63, 2001. © 2001 Wiley‐Liss, Inc.
Keywords: endothelin‐1, focal segmental glomerulosclerosis, puromycin aminonucleoside
references
- 1. Yanagisawa M, Kurihara H, Kimura S. 1988. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415. [DOI] [PubMed] [Google Scholar]
- 2. Kohan DE. 1998. Angiotensin II and endothelin in chronic glomerulonephritis. Kidney Int 54:646–647. [DOI] [PubMed] [Google Scholar]
- 3. Herman WH, Emancipator SN, Rhoten RLP, Simonson MS. 1998. Vascular and glomerular expression of endothelin‐1 in normal human kidney. Am J Physiol 275:F8–F17. [DOI] [PubMed] [Google Scholar]
- 4. Bruzzi I, Corna D, Zoja C, et al. 1997. Time course and localization of endothelin‐1 gene expression in a model of renal disease progression. Am J Pathol 151:1241–1247. [PMC free article] [PubMed] [Google Scholar]
- 5. Brochu E, Lacasse S, Moreau C, et al. 1999. Endothelin ET(A) receptor blockade prevents the progression of renal failure and hypertension in uraemic rats. Nephrol Dial Transplant 14:1881–1888. [DOI] [PubMed] [Google Scholar]
- 6. Roccatello D, Mosso R, Ferro M, et al. 1994. Urinary endothelin in glomerulonephritis patients with normal renal function. Clin Nephrol 41:323–330. [PubMed] [Google Scholar]
- 7. Grond J, Koudstaal J, Elema JD. 1985. Mesangial function and glomerular sclerosis in rats with aminonucleoside nephrosis. Kidney Int 27:405–410. [DOI] [PubMed] [Google Scholar]
- 8. Chen HC, Guh JY, Shin SJ, Tsai JH, Lai YH. 2000. Reactive oxygen species enhances endothelin‐1 production of diabetic rat glomeruli in vitro and in vivo. J Lab Clin Med 135:309–315. [DOI] [PubMed] [Google Scholar]
- 9. Shichiri M, Hirata Y, Ando K, et al. 1990. Plasma endothelin levels in hypertension and chronic renal failure. Hypertension 15:493–496. [DOI] [PubMed] [Google Scholar]
- 10. Vlachojannis J, Tsakas S, Petropoulou C, Kurtz P. 1997. Increased renal excretion of endothelin‐1 in nephritic patients. Nephrol Dial Transplant 12:470–473. [DOI] [PubMed] [Google Scholar]
- 11. Furness PN, Harris K. 1994. An evaluation of experimental models of glomerulonephritis. Int J Exp Pathol 75:9–22. [PMC free article] [PubMed] [Google Scholar]
- 12. Wolf SC, Smoltczyk H, Brehm BR, Erley CM, Risler T. 1998. Endothelin‐1 and endothelin‐3 levels in different types of glomerulonephritis. J Cardiovasc Pharmacol 31:S482–S485. [DOI] [PubMed] [Google Scholar]
- 13. Modesti PA, Cecioni I, Migliorini A, et al. 1998. Increased renal endothelin formation is associated with sodium retention and increased free water clearance. Am J Physiol 275:H1070–H1077. [DOI] [PubMed] [Google Scholar]
- 14. Chu TS, Wu MS, Hsieh BS. 1998. Urinary endothelin‐1 in patients with renal disease. J Formos Med Assoc 97:667–672. [PubMed] [Google Scholar]
- 15. Nakamura T, Ebihara I, Fukui M, Takahashi T, Tomino Y, Koide H. 1993. Altered glomerular steady‐state levels of tumor necrosis factor‐alpha mRNA during nephrotic and sclerotic phases of puromycin aminonucleoside nephrosis in rats. Clin Sci (Colch) 84:349–356. [DOI] [PubMed] [Google Scholar]
- 16. Yang CW, Hsueh S, Wu MS, et al. 1997. Glomerular transforming growth factor‐beta1 mRNA as a marker of glomerulosclerosis‐application in renal biopsies. Nephron 77:290–297. [DOI] [PubMed] [Google Scholar]
- 17. Kohan DE. 1993. Endothelins in the kidney: physiology and pathophysiology. Am J Kidney Dis 22:493–510. [DOI] [PubMed] [Google Scholar]
- 18. Kohan DE. 1997. Endothelins in the normal and diseased kidney. Am J Kidney Dis 29:2–26. [DOI] [PubMed] [Google Scholar]
- 19. Barton M, Vos I, Shaw S, et al. 2000. Dysfunctional renal nitric oxide synthase as a determinant of salt‐sensitive hypertension: mechanisms of renal artery endothelial dysfunction and role of endothelin for vascular hypertrophy and glomerulosclerosis. J Am Soc Nephrol 11:835–845. [DOI] [PubMed] [Google Scholar]
- 20. Hocher B, Thone‐Reineke C, Rohmeiss P, et al. 1997. Endothelin‐1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. J Clin Invest 99:1380–1389. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Gomez‐Garre D, Ruiz‐Ortega M, Ortego M, et al. 1996. Effects of interactions of endothelin‐1 and angiotensin II on matrix protein expression and synthesis and mesangial cell growth. Hypertension 27:885–892. [DOI] [PubMed] [Google Scholar]