This project will test the central hypothesis that increased HO-1 in the renal medulla lowers blood pressure in angiotensin II (Ang II) hypertension by inhibiting Ang II induced increases in NADPH oxidase and superoxide production via billirubin and CO dependent mechanisms. This will be accomplished by a combined integrative physiological and in vitro approach.
The specific aims of this proposal are 1) To test the hypothesis that chronic decreases in renal medullary HO-1 levels enhance and chronic induction of renal medullary HO-1 attenuates Ang II mediated blunting of renal pressure- natriuresis and lower blood pressure, 2) To test the hypothesis that chronic changes in HO-1 can alter the Ang II mediated increase in NADPH oxidase and superoxide production in the renal medulla, 3) To test the hypothesis that HO-1 metabolites CO and bilirubin are essential in buffering Ang II mediated increases in NADPH oxidase, superoxide production and blood pressure, 4) To test the hypothesis that chronic increases in HO-1 levels specifically in the thick ascending loop of Henle (TALH) can reduce Ang II mediated alterations in renal pressure-natriuresis and lower blood pressure via decreasing Ang II mediated NADPH oxidase activity and superoxide anion production in the TALH. Experiments in this proposal will be performed in mice in which HO inhibitors and inducers of HO-1 will be chronically infused via intrarenal medullary interstitial catheters in mice receiving chronic infusions of Ang II. Experiments in Aim 4 will be conducted on a novel transgenic mouse model in which the human HO-1 isoform is specifically expressed in TALH cells. Experiments in this proposal will be performed in mice in which HO inhibitors or inducers will be chronically infused via intrarenal medullary interstitial catheters in mice receiving chronic infusions of Ang II. Further studies will determine the role of HO-1 and its metabolites, CO and bilirubin, on Ang II-mediated superoxide production in isolated tubule segments and cultured cells. The research proposed in this application is significant because it will provide new insights into the mechanism of how induction of HO-1 in the renal medulla can reduce oxidative stress and lower blood pressure in hypertension. Understanding of the mechanisms underlying the anti-hypertensive actions of HO-1 in the renal medulla may provide novel therapeutic options for certain hypertensive patient populations which are resistant to current therapies.

Public Health Relevance

The research proposed in this application is significant because it will provide new insights into the mechanism of how the kidney can regulate blood pressure and how alterations in kidney function can lead to high blood pressure or hypertension. A better understanding of the how the kidney controls blood pressure may provide an opportunity to develop new drugs to treat people with hypertension who are resistant to current therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088421-05
Application #
8316332
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2008-09-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$329,670
Indirect Cost
$106,920
Name
University of Mississippi Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Stec, David E; John, Kezia; Trabbic, Christopher J et al. (2016) Bilirubin Binding to PPARα Inhibits Lipid Accumulation. PLoS One 11:e0153427
Hinds Jr, Terry D; Burns, Katherine A; Hosick, Peter A et al. (2016) Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3β Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) α. J Biol Chem 291:25179-25191
O'Brien, Luke; Hosick, Peter A; John, Kezia et al. (2015) Biliverdin reductase isozymes in metabolism. Trends Endocrinol Metab 26:212-20
George, Eric M; Stout, Jacob M; Stec, David E et al. (2015) Heme oxygenase induction attenuates TNF-α-induced hypertension in pregnant rodents. Front Pharmacol 6:165
Hosick, P A; AlAmodi, A A; Storm, M V et al. (2014) Chronic carbon monoxide treatment attenuates development of obesity and remodels adipocytes in mice fed a high-fat diet. Int J Obes (Lond) 38:132-9
Stec, David E; Storm, Megan V; Pruett, Brandon E et al. (2013) Antihypertensive actions of moderate hyperbilirubinemia: role of superoxide inhibition. Am J Hypertens 26:918-23
Stout, Jacob M; Gousset, Monette U; Drummond, Heather A et al. (2013) Sex-specific effects of heme oxygenase-2 deficiency on renovascular hypertension. J Am Soc Hypertens 7:328-35
George, Eric M; Hosick, Peter A; Stec, David E et al. (2013) Heme oxygenase inhibition increases blood pressure in pregnant rats. Am J Hypertens 26:924-30
Csongradi, Eva; Storm, Megan V; Stec, David E (2012) Renal Inhibition of Heme Oxygenase-1 Increases Blood Pressure in Angiotensin II-Dependent Hypertension. Int J Hypertens 2012:497213
Csongradi, Eva; Juncos, Luis A; Drummond, Heather A et al. (2012) Role of carbon monoxide in kidney function: is a little carbon monoxide good for the kidney? Curr Pharm Biotechnol 13:819-26

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