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(Hypertension. 1997;29:1178-1185.)
© 1997 American Heart Association, Inc.
Articles |
Endothelin-1 Upregulation in the Kidney of Uninephrectomized Spontaneously Hypertensive Rats and Its Modification by the Angiotensin-Converting Enzyme Inhibitor Quinapril
From the Renal Research Laboratory Fundación Jiménez Díaz, Universidad Autónoma, and the Department of Pathology (J.B.), Hospital Clínico, Universidad Complutense, Madrid, Spain.
Correspondence to Jesús Egido, MD, Servicio Nefrologia, Fundación Jiménez Díaz, Avda Reyes Católicos, 2, 28040 Madrid. E-mail egido{at}alpha2.ft.uam.es
Abstract Endothelin (ET-1) is a potent vasoconstrictor that plays an important role in the control of renal circulation and tubular function. The contribution of this peptide to the pathogenesis of systemic hypertension and renal failure remains largely undefined. In spontaneously hypertensive rats (SHR) uninephrectomized at 20 weeks of age (UNX-SHR) and followed until 45 weeks of age, we determined ET-1 gene expression in renal tissue by reverse transcription–polymerase chain reaction and its localization by in situ hybridization in paraffin-embedded kidney sections. Age-matched SHR and normotensive Wistar-Kyoto (WKY) rats were chosen as controls. At the end of the follow-up, UNX-SHR had high systolic blood pressure, intense proteinuria, mesangial expansion, focal and segmental glomerular sclerosis, and tubulointerstitial lesions. In relation to WKY and SHR, UNX-SHR exhibited an increase in ET-1 gene expression in renal cortex and medulla. By in situ hybridization and immunoperoxidase staining, an overexpression of ET-1 gene and protein were seen in mesangial and glomerular epithelial cells and in some proximal tubules and vessels. Angiotensin-converting enzyme (ACE) activity was significantly increased in the renal brush border. Since in mesangial cells, angiotensin II induces ET-1 synthesis, a group of UNX-SHR received the ACE inhibitor quinapril from the time of UNX. These animals had a decrease in blood pressure, proteinuria, and serum and brush border ACE activity and in the expression and synthesis of ET-1 in all renal areas. On the whole, these data show that UNX-SHR have an upregulation of ET-1 gene and protein in several structures of the kidney compared with SHR and WKY rats. Quinapril diminished ACE activity and ET-1 expression and synthesis coincidentally with an improvement in proteinuria and morphological lesions. The beneficial effects of ACE inhibitors may be due to the diminution of both angiotensin II and ET-1 generation.
Key Words: kidney • rats, inbred SHR • endothelin-1 • ACE inhibition
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