The goal of Project 2 in this PPG is to understand renal cellular metabolic mechanisms of salt-sensitive hypertension. Recent work, including work in this project in the current cycle of PPG, has discovered a novel role of fumarase (Fh1) and fumarate metabolism in hypertension in the Dahl salt-sensitive (SS) rat. Fumarase primarily catalyzes the conversion of fumarate to malate in the tricarboxylic acid (TCA) cycle in mitochondria. Fumarase enzyme activity is lower in the kidneys of SS rats than SS.13BN or Sprague-Dawley (SD) rats, and fumarate is higher and malate is lower in the kidneys of SS rats. Transgenic over-expression of fumarase on the background of SS rat (SSTgFh1) attenuates hypertension. Intravenous infusion of a fumarate precursor in SS.13BN rats exacerbates hypertension. It remains unknown 1) what mechanisms mediate the effect of fumarase-related metabolites on salt-sensitive hypertension, and 2) whether blood pressure salt-sensitivity in humans is associated with abnormalities in intermediary metabolism.
Aim 1 of the proposed study will test a novel hypothesis that fumarase insufficiency contributes to salt-sensitive hypertension in SS rats in part by reducing arginine regeneration and nitric oxide (NO) levels in the kidney.
Aim 2 studies are designed to identify metabolites associated with blood pressure in humans on low- or high-sodium intake. The proposed study could provide novel insights into the mechanisms by which fundamental metabolism contributes to hypertension. In addition, it could identify specific metabolic intermediaries that might be important for mediating the effect of dietary salt intake on blood pressure in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL116264-06
Application #
9417467
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
OH, Youngsuk
Project Start
Project End
Budget Start
2018-01-01
Budget End
2019-06-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Type
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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Evans, Louise C; Petrova, Galina; Kurth, Theresa et al. (2017) Increased Perfusion Pressure Drives Renal T-Cell Infiltration in the Dahl Salt-Sensitive Rat. Hypertension 70:543-551
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Dayton, Alex; Exner, Eric C; Bukowy, John D et al. (2016) Breaking the Cycle: Estrous Variation Does Not Require Increased Sample Size in the Study of Female Rats. Hypertension 68:1139-1144
Huang, Baorui; Cheng, Yuan; Usa, Kristie et al. (2016) Renal Tumor Necrosis Factor ? Contributes to Hypertension in Dahl Salt-Sensitive Rats. Sci Rep 6:21960
Miller, Bradley; Palygin, Oleg; Rufanova, Victoriya A et al. (2016) p66Shc regulates renal vascular tone in hypertension-induced nephropathy. J Clin Invest 126:2533-46
Zheleznova, Nadezhda N; Yang, Chun; Cowley Jr, Allen W (2016) Role of Nox4 and p67phox subunit of Nox2 in ROS production in response to increased tubular flow in the mTAL of Dahl salt-sensitive rats. Am J Physiol Renal Physiol 311:F450-8

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