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 #
5P01HL116264-09
Application #
10075949
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
OH, Youngsuk
Project Start
2013-09-01
Project End
2021-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
9
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Type
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Abais-Battad, Justine M; Mattson, David L (2018) The Influence of Dietary Protein on Dahl Salt-Sensitive Hypertension: a Potential Role for Gut Microbiota. Am J Physiol Regul Integr Comp Physiol :
Staruschenko, Alexander (2018) Beneficial Effects of High Potassium: Contribution of Renal Basolateral K+ Channels. Hypertension 71:1015-1022
Cheng, Yuan; Song, Haiying; Pan, Xiaoqing et al. (2018) Urinary Metabolites Associated with Blood Pressure on a Low- or High-Sodium Diet. Theranostics 8:1468-1480
Kumar, Vikash; Evans, Louise C; Kurth, Theresa et al. (2018) Therapeutic Suppression of mTOR (Mammalian Target of Rapamycin) Signaling Prevents and Reverses Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats. Hypertension :HYPERTENSIONAHA11812378
Cowley Jr, Allen W (2018) Chrm3 Gene and M3 Muscarinic Receptors Contribute to Salt-Sensitive Hypertension. Hypertension 72:588-591
Palygin, Oleg; Pochynyuk, Oleh; Staruschenko, Alexander (2018) Distal tubule basolateral potassium channels: cellular and molecular mechanisms of regulation. Curr Opin Nephrol Hypertens 27:373-378
Ilatovskaya, Daria V; Blass, Gregory; Palygin, Oleg et al. (2018) A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease. J Am Soc Nephrol 29:1917-1927
Mattson, David L (2018) Heat stress nephropathy and hyperuricemia. Am J Physiol Renal Physiol 315:F757-F758
Abais-Battad, Justine M; Lund, Hayley; Fehrenbach, Daniel J et al. (2018) Rag1-null Dahl SS rats reveal that adaptive immune mechanisms exacerbate high protein-induced hypertension and renal injury. Am J Physiol Regul Integr Comp Physiol 315:R28-R35
Bukowy, John D; Dayton, Alex; Cloutier, Dustin et al. (2018) Do computers dream of electric glomeruli? Kidney Int 94:635

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