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1 and Nitric Oxide is Altered in Salt-Sensitive Hypertension
1 Department of Medicine, and Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Medicine, Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: psanders{at}uab.edu.
The study of salt-sensitive hypertension has been facilitated by development of genetic models, especially the Dahl/Rapp salt-sensitive (S) rat. S rats rapidly become hypertensive after initiation of a diet containing 8.0% NaCl and subsequently develop arteriolonephrosclerosis and renal failure, while the salt-resistant (R) strain remains normotensive on the same diet. The purpose of the present study was to use these strains to demonstrate the interactions between transforming growth factor-
1 (TGF-1) and nitric oxide (NO). Young, male S and R rats were fed for four days diets that contained either 0.3% or 8.0% NaCl. An increase in dietary salt increased kinase activities of both p38 MAPK and p42/44 MAPK in cytoplasmic extracts from aortic rings and isolated glomeruli from both strains. Inhibition of either pathway with PD-098059 or SB-203580 decreased production of TGF-1 and nitrate plus nitrite (NOx). In both strains, production of active TGF-1 and NOx linearly correlated. Incubation of aortic rings and isolated glomeruli with the NO donor, NOR3, decreased TGF-1 levels, while the NO synthase inhibitor, L-NAME, increased production. The inhibitory effect of NO on production of TGF-1 was reduced in preparations from S rats. Although a close inter-relationship existed between TGF-1 and NO in both strains, production of TGF-1 was increased in prehypertensive S rats and was further exaggerated with the increase in dietary salt intake. Augmented vascular and glomerular production of TGF-1 and diminished NO may contribute to the development of hypertensive nephrosclerosis in S rats.
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