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The interrelationship between TGF-₁ and nitric oxide is altered in salt-sensitive hypertension

Nephrology Research and Training Center, Comprehensive Cancer Center, and Cell Adhesion and Matrix Research Center, Division of Nephrology, Department of Medicine, and Department of Physiology & Biophysics, University of Alabama at Birmingham, Birmingham 35294-0007; and Department of Veterans Affairs Medical Center, Birmingham, Alabama 35233

Submitted 7 May 2003 ; accepted in final form 7 July 2003

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, whereas 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 4 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 (NO_x). In both strains, production of active TGF-₁ and NO_x linearly correlated. Incubation of aortic rings and isolated glomeruli with the NO donor NOR3 decreased TGF-₁ levels, whereas the NO synthase inhibitor N-nitro-L-arginine methyl ester increased production. The inhibitory effect of NO on production of TGF-₁ was reduced in preparations from S rats. Although a close interrelationship 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.

dietary salt; transforming growth factor-₁; salt sensitivity; Dahl/Rapp rat

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