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

This study examined the role of transforming growth factor-β (TGF-β) in altering the glomerular permeability to albumin (Palb) during hypertension development in Dahl salt-sensitive (Dahl S) rats and whether TGF-β acts by inhibiting the glomerular production of 20-HETE. The results indicate that the renal expression of TGF-β doubles in Dahl S rats fed a high-salt diet for 7 days, and this is associated with a marked rise in Palb 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-β neutralizing antibody prevented the increase in Palb 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-β1 (10 ng/mL) for 15 minutes increased Palb 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 Palb and opposed the effects of TGF-β to increase Palb. These studies indicate that upregulation of the glomerular formation of TGF-β may contribute to the development of proteinuria and glomerular injury early in hypertension development in Dahl S rats by increasing Palb through inhibition of the glomerular production of 20-HETE.