ENDOTHELIN-1 UP-REGULATION IN THE KIDNEY OF UNINEPHRECTOMIZED SPONTANEOUSLY HYPERTENSIVE RATS AND ITS MODIFICATION BY THE ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR QUINAPRIL

Endothelin (ET-1) is a patent vasoconstrictor that plays an important role in the control of renal circulation and tubular function. The con tribution of this peptide to the pathogenesis of systemic hypertension and renal failure remains largely undefined. In spontaneously hyperte nsive rats (SHR) uninephrectomized at 20 weeks of age (UNX-SHR) and fo llowed until 45 weeks of age, we determined ET-1 gene expression in re nal tissue by reverse transcription-polymerase chain reaction and its localization by in situ hybridization in paraffin-embedded kidney sect ions, Age-matched SI-IR and normotensive Wistar-Kyoto (WKY) rats were chosen as controls. At the end of the follow-up, UNX-SHR had high syst olic blood pressure, intense proteinuria, mesangial expansion, focal a nd segmental glomerular sclerosis, and tubulointerstitial lesions. In relation to WKY and SHR, UNX-SHR exhibited an increase in ET-I gene ex pression in renal cortex and medulla. By in situ hybridization and imm unoperoxidase staining, an overexpression of ET-l gene and protein wer e seen In mesangial and glomerular epithelial cells and in some proxim al tubules and vessels. Angiotensin-converting enzyme (ACE) activity w as significantly increased in the renal brush border. Since In mesangi al cells, angiotensin II induces ET-I synthesis, a group of UNX-SHR re ceived the ACE inhibitor quinapril from the time of UNX. These animals had a decrease in blood pressure, proteinuria: and serum and brush bo rder ACE activity and in the expression and synthesis of ET-l in all r enal areas. On the whole, these data show: that UNX-SHR have an upregu lation of ET-I gene and protein in several structures of the kidney co mpared with SHR and WKY rats. Quinapril diminished ACE activity and ET -1 expression and synthesis coincidentally with an improvement in prot einuria and morphological lesions. The beneficial effects of ACE Inhib itors may be due to the diminution of both angiotensin II and ET-I gen eration.