Diabetes and hypertension are the leading causes of endstage renal disease (ESRD). Despite effective medications, the incidence of ESRD is increasing and the associated costs now exceed $15 billion a year. The renal expression of TGF-beta is elevated in hypertension and diabetes and blockade of this pathway decreases renal fibrosis. However, the factors that increase the production of TGF-beta and its role in the initiation of renal disease remain to be determined. In preliminary experiments, we found that inducing the renal formation of 20-HETE or blocking the actions of TGF-beta attenuate the development of renal disease in Dahl S rats. TGF-beta also directly increased the permeability of glomeruli to albumin (Palb) and inhibited the glomerular formation of 20-HETE. Thus, this proposal will evaluate the hypothesis that a deficiency in the renal formation of 20-HETE leads to elevations in glomerular capillary pressure (Pgc) and the renal expression of TGF-beta in Dahl S rats and that the increase in TGF-beta triggers the development of proteinuria and renal disease by increasing Palb.
Specific Aim 1 will determine the relationships between Pgc, the renal expression of TGF-beta, Palb and the development of renal disease and the effects of servocontrol of renal perfusion pressure (RPP) on these responses.
Specific Aim 2 will determine if the reduced production of 20-HETE contributes to the increases in Pgc, TGF-beta and the development of renal disease.
Specific Aim 3 will examine the interactions between TGF-beta and 20-HETE in the regulation of Palb and the mechanism by which TGF-beta inhibits the formation of 20-HETE.
Specific Aim 4 will determine whether Palb is altered early in the development of hypertension and the role of TGF-beta in mediating this response. These studies will employ an array of techniques, ranging from direct measurement of Pgc, LC/MS measurement of 20-HETE and chronic servocontrol of RPP to measurements of Palb and Ca++ in isolated glomeruli. They will also utilize a newly-developed congenic strain of Dahl S rats in which renal 20-HETE levels are elevated and novel inhibitors and antibodies that can manipulate the 20-HETE and TGF-beta pathways in vivo. These translational studies will provide important new information on the role of TGF-beta, 20-HETE and Pgc in the pathogenesis of hypertension-induced renal disease and may be applicable to diabetes and other models of renal disease as well in which TGF-beta and Pgc are also elevated.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL036279-27
Application #
8245057
Study Section
Special Emphasis Panel (ZRG1-CVS-G (90))
Program Officer
OH, Youngsuk
Project Start
1986-07-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
27
Fiscal Year
2012
Total Cost
$409,385
Indirect Cost
$135,549
Name
University of Mississippi Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
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Orozco, Ludwig D; Liu, Huiling; Perkins, Eddie et al. (2013) 20-Hydroxyeicosatetraenoic acid inhibition attenuates balloon injury-induced neointima formation and vascular remodeling in rat carotid arteries. J Pharmacol Exp Ther 346:67-74
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