Dopamine promotes an increase in renal sodium excretion by activating dopamine D1-like receptors in proximal tubules (PTs) and causing inhibition of Na,H-exchanger and Na,K-ATPase. We have shown that the ability of dopamine to inhibit these sodium transporters is reduced in old rats and the natriuretic response to dopamine is also diminished in older animals. This is due to a defective D1-like receptor-coupled signal transduction pathway, caused by hyper-serine-phosphorylation of D1A receptor in old rats, and an increase in protein kinase C (PKC) activity in the PTs. G-protein coupled receptor kinases (GRKs) are known to phosphorylate and desensitize dopamine D1 receptors. In preliminary studies, we found an increase in oxidative stress in old rats and antioxidant supplementation lowered oxidative stress, decreased basal PKC activity, and restored natriuretic response to D1 receptor activation. This application will test the hypothesis that increase in oxidative stress causes increase in PKC activity, which via activation of GRKs, produces an increase in the basal serine-phosphorylation of D1A receptors, causing it's uncoupling from G-proteins. Experiments are designed to determine the mechanism of oxidative stress-induced increase in basal PKC activity, role of specific PKC isoforms (beta & delta) and GRK isoform (GRK-2) in hyper-serine-phosphorylation of D1A receptor and G-protein uncoupling in proximal tubular cell cultures exposed to oxidants and in old rats. In order to examine the role of oxidative stress in D1A receptor G-protein uncoupling in old rats, animals will be given antioxidants supplementation followed by measurements of oxidant levels, PKC and GRK activities and D1A receptor signaling and natriuretic response to D1-like agonist, fenoldopam. The results will allow us to identify the molecular basis of renal D1 receptor dysfunction in old rats. Our findings will have a far reaching significance as it relates to the use of antioxidants in restoring defective G-protein coupled receptor function and drug responsiveness associated with increased oxidative stress in aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025056-03
Application #
7257008
Study Section
Special Emphasis Panel (ZRG1-RUS-D (02))
Program Officer
Kohanski, Ronald A
Project Start
2005-08-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$281,609
Indirect Cost
Name
University of Houston
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
036837920
City
Houston
State
TX
Country
United States
Zip Code
77204
George, Liza E; Lokhandwala, Mustafa F; Asghar, Mohammad (2012) Novel role of NF-?B-p65 in antioxidant homeostasis in human kidney-2 cells. Am J Physiol Renal Physiol 302:F1440-6
Chugh, Gaurav; Lokhandwala, Mustafa F; Asghar, Mohammad (2012) Altered functioning of both renal dopamine D1 and angiotensin II type 1 receptors causes hypertension in old rats. Hypertension 59:1029-36
Asghar, Mohammad; Tayebati, Seyed K; Lokhandwala, Mustafa F et al. (2011) Potential dopamine-1 receptor stimulation in hypertension management. Curr Hypertens Rep 13:294-302
Chugh, Gaurav; Lokhandwala, Mustafa F; Asghar, Mohammad (2011) Oxidative stress alters renal D1 and AT1 receptor functions and increases blood pressure in old rats. Am J Physiol Renal Physiol 300:F133-8
Banday, Anees Ahmad; Lokhandwala, Mustafa F (2009) Inhibition of natriuretic factors increases blood pressure in rats. Am J Physiol Renal Physiol 297:F397-402
George, Liza; Lokhandwala, Mustafa F; Asghar, Mohammad (2009) Exercise activates redox-sensitive transcription factors and restores renal D1 receptor function in old rats. Am J Physiol Renal Physiol 297:F1174-80
Asghar, Mohammad; Chugh, Gaurav; Lokhandwala, Mustafa F (2009) Inflammation compromises renal dopamine D1 receptor function in rats. Am J Physiol Renal Physiol 297:F1543-9
Banday, Anees Ahmad; Lokhandwala, Mustafa F (2008) Oxidative stress-induced renal angiotensin AT1 receptor upregulation causes increased stimulation of sodium transporters and hypertension. Am J Physiol Renal Physiol 295:F698-706
Banday, Anees Ahmad; Lokhandwala, Mustafa F (2008) Loss of biphasic effect on Na/K-ATPase activity by angiotensin II involves defective angiotensin type 1 receptor-nitric oxide signaling. Hypertension 52:1099-105
Asghar, Mohammad; Chillar, Annirudha; Lokhandwala, Mustafa F (2008) Renal proximal tubules from old Fischer 344 rats grow into epithelial cells in cultures and exhibit increased oxidative stress and reduced D1 receptor function. Am J Physiol Cell Physiol 295:C1326-31

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