The Inter-relationship Between TGF-ß1 and Nitric Oxide is Altered in Salt-Sensitive Hypertension

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-ß1 (TGF-ß1) 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-ß1 and nitrate plus nitrite (NO x). In both strains, production of active TGF-ß1 and NO x linearly correlated. Incubation of aortic rings and isolated glomeruli with the NO donor, NOR3, decreased TGF-ß1 levels, while the NO synthase inhibitor, L-NAME, increased production. The inhibitory effect of NO on production of TGF-ß1 was reduced in preparations from S rats. Although a close interrelationship existed between TGF-ß1 and NO in both strains, production of TGF-ß1 was increased in prehypertensive S rats and was further exaggerated with the increase in dietary salt intake. Augmented vascular and glomerular production of TGF-ß1 and diminished NO may contribute to the development of hypertensive nephrosclerosis in S rats.