Published Online
on February 21, 2005

A more recent version of this article appeared on April 1, 2005

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Submitted on October 11, 2004
Revised on November 3, 2004

Transforming Growth Factor-, 20-HETE Interaction, and Glomerular Injury in Dahl Salt-Sensitive Rats

Annette J. Dahly-Vernon; Mukut Sharma; Ellen T. McCarthy; Virginia J. Savin; Steven R. Ledbetter; and Richard J. Roman^*

From the Departments of Physiology, Medicine, and Kidney Disease Center (A.J.D.-V., M.S., E.T.M., V.J.S., R.J.R.), Medical College of Wisconsin, Milwaukee; and Genzyme Corporation (S.R.L.), Framingham, Mass.

^* To whom correspondence should be addressed. E-mail: rroman{at}mcw.edu.

Abstract--This study examined the role of transforming growth factor- (TGF-) in altering the glomerular permeability to albumin (P_alb) during hypertension development in Dahl salt-sensitive (Dahl S) rats and whether TGF- acts by inhibiting the glomerular production of 20-HETE. The results indicate that the renal expression of TGF- doubles in Dahl S rats fed a high-salt diet for 7 days, and this is associated with a marked rise in P_alb from 0.19±0.04 to 0.75±0.01 and changes in the ultrastructure of the glomerular filtration barrier. Chronic treatment of Dahl S rats with a TGF- neutralizing antibody prevented the increase in P_alb and preserved the structure of glomerular capillaries. It had no effect on the rise in blood pressure produced by the high-salt diet. In other studies, preincubation of glomeruli isolated from Sprague Dawley rats with TGF-1 (10 ng/mL) for 15 minutes increased P_alb from 0.01±0.01 to 0.60±0.02. This was associated with inhibition of the glomerular production of 20-HETE from 221±11 to 3.4±0.5 µg per 30 minutes per milligram of protein. Pretreatment of Sprague Dawley glomeruli with a stable analog of 20-HETE, 20-hydroxyeicosa-5(Z), 14(Z)-dienoic acid, reduced baseline P_alb and opposed the effects of TGF- to increase P_alb. These studies indicate that upregulation of the glomerular formation of TGF- may contribute to the development of proteinuria and glomerular injury early in hypertension development in Dahl S rats by increasing P_alb through inhibition of the glomerular production of 20-HETE.

Key words: transforming growth factors • kidney • hypertension, renal

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