Transforming growth factor-beta, 20-HETE interaction, and glomerular injury in Dahl salt-sensitive rats.
This study examined the role of transforming growth factor-beta (TGF-beta) in altering the glomerular permeability to albumin (P(alb)) during hypertension development in Dahl salt-sensitive (Dahl S) rats and whether TGF-beta acts by inhibiting the glomerular production of 20-HETE. The results indicate that the renal expression of TGF-beta 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-beta 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-beta1 (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 mug 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-beta to increase P(alb). These studies indicate that upregulation of the glomerular formation of TGF-beta 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.
Dahly-Vernon
Annette J
AJ
Department of Physiology, and Kidney Disease Center, Medical College of Wisconsin, Milwaukee, WI 53226-4801, USA.
Sharma
Mukut
M
McCarthy
Ellen T
ET
Savin
Virginia J
VJ
Ledbetter
Steven R
SR
Roman
Richard J
RJ
D000818:Animals; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors*; D006973:Hypertension / Q000209:etiology / Q000378:metabolism*; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology*; D008854:Microscopy, Electron; D010539:Permeability / Q000187:drug effects; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000493:pharmacokinetics*; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D006893:Hydroxyeicosatetraenoic Acids; D017673:Sodium Chloride, Dietary; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012710:Serum Albumin, Bovine; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid