Renal oxidative stress is determined by the balance between the primary source of superoxide, NADPH oxidase (NOX) and intrarenal enzymes that scavenge superoxide, superoxide dismutases (SOD). Renal oxidative stress contributes to the development of systemic hypertension by alterations in renal function, including vasoconstriction, increased solute and electrolyte retention and tubular dysfunction. The reabsorption of sodium is the major energy requirement for the kidney and the efficient use of oxygen for Na+ transport is reduced during oxidative stress. We propose to test the effects of oxidative stress on oxygen usage in the kidney and to determine the mechanism(s) by which Na+ reabsorption requires greater oxygen. In a series of experiments measuring in vivo single nephron function in gene deleted mice and in vitro measurements of PT cell function we will identify specific sites of oxygen utilization dysfunction.
In aim 1, we will test the hypothesis that the inefficient use of oxygen is dependent on the balance between NOX and SOD, by using single gene deleted mice.
In aim 2 we will examine the mechanism of the inefficient use of oxygen, focusing on Na+ reabsorption in the proximal tubule (PT). In a series of both in vivo and in vitro experiments, we will evaluate the cellular integrity and function of the PT during acute and chronic oxidative stress. We will examine paracellular and transcellular function in PT cells.
In aim 3 we will test the hypothesis that the increased blood pressure associated with angiotensin II-induced oxidative stress is dependent on increased generation of adenosine and enhancement of tubuloglomerular feedback, leading to decreased renal blood flow and increased renal vascular resistance. These studies should provide new and valuable information on the relationship between oxygen usage in the kidney and the pro-vasoconstriction events associated with oxidative stress and hypertension. Project Narrative: Ischemia, the lack of efficient oxygen delivery is the most common cause of acute renal failure and renal artery stenosis causing renal ischemia is the second most common cause of secondary hypertension. These conditions are accompanied by severe oxidative stress within the kidneys. Therefore, knowledge of the interaction of oxidants and oxygen within the kidney will provide insight into the causes of these renal diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089583-05
Application #
8266338
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2008-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$379,913
Indirect Cost
$132,413
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Pei, Lei; Solis, Glenn; Nguyen, Mien T X et al. (2016) Paracellular epithelial sodium transport maximizes energy efficiency in the kidney. J Clin Invest 126:2509-18
Wang, Cheng; Luo, Zaiming; Kohan, Donald et al. (2015) Thromboxane prostanoid receptors enhance contractions, endothelin-1, and oxidative stress in microvessels from mice with chronic kidney disease. Hypertension 65:1055-63
Li, Lingli; Feng, Di; Luo, Zaiming et al. (2015) Remodeling of Afferent Arterioles From Mice With Oxidative Stress Does Not Account for Increased Contractility but Does Limit Excessive Wall Stress. Hypertension 66:550-6
Friederich-Persson, Malou; Welch, William J; Luo, Zaiming et al. (2014) Angiotensin II reduces transport-dependent oxygen consumption but increases transport-independent oxygen consumption in immortalized mouse proximal tubular cells. Adv Exp Med Biol 812:157-63
Hansell, Peter; Welch, William J; Blantz, Roland C et al. (2013) Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension. Clin Exp Pharmacol Physiol 40:123-37
Lee, Dexter L; Bell, Tracy D; Bhupatkar, Jenny et al. (2012) Adenosine A1-receptor knockout mice have a decreased blood pressure response to low-dose ANG II infusion. Am J Physiol Regul Integr Comp Physiol 303:R683-8
Lai, En Yin; Luo, Zaiming; Onozato, Maristela L et al. (2012) Effects of the antioxidant drug tempol on renal oxygenation in mice with reduced renal mass. Am J Physiol Renal Physiol 303:F64-74
Lai, En Yin; Solis, Glenn; Luo, Zaiming et al. (2012) p47(phox) is required for afferent arteriolar contractile responses to angiotensin II and perfusion pressure in mice. Hypertension 59:415-20
Lai, En Yin; Wellstein, Anton; Welch, William J et al. (2011) Superoxide modulates myogenic contractions of mouse afferent arterioles. Hypertension 58:650-6
Tassi, Elena; McDonnell, Kevin; Gibby, Krissa A et al. (2011) Impact of fibroblast growth factor-binding protein-1 expression on angiogenesis and wound healing. Am J Pathol 179:2220-32

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