The goal of the work in this Project is to understand the mechanisms of salt-sensitive hypertension. Salt-induced hypertension and renal injury in Dahl Salt-Sensitive (SS) rats fed a high salt diet proceeds in two phases. An initial, primary rise of blood pressure (BP), which is not dependent upon inflammation, is followed by a more dramatic, secondary rise of BP which is accompanied by increased infiltration of immune cells into the kidney and culminates in `malignant hypertension'. Pharmacological and genetic approaches that reduce renal immune cell infiltration attenuate this secondary phase of salt-induced hypertension and renal injury in SS rats. These observations parallel data obtained from hypertensive patients and indicate that immune cells in the kidney play a key role in the pathology of hypertension by amplifying the disease process, but the mechanisms leading to the infiltration and activation of immune cells in the kidney are unknown and are the focus of this research proposal. In the present proposal, we present intriguing data indicating that an initial elevation of renal perfusion pressure (RPP) elicits a molecular cascade involving increased H2O2, increased mTORC1, and activation of the NLRP3 inflammasome. Moreover, our data indicate that H2O2 and mTORC1 can activate the inflammasome which mediates infiltration of immune cells into the kidney. Based on these data, we hypothesize that malignant hypertension and renal damage in SS rats is triggered by a primary elevation of RPP which leads to an associated increase of renal oxidative stress (H2O2 from Nox4) and mTORC1. The altered H2O2 and mTORC1 activate the NLRP3 inflammasome which mediates innate and adaptive immune mechanisms. The resulting infiltrating immune cells then release additional H2O2 from Nox2 in a positive feedback cycle that further enhances hypertension and renal damage. This hypothesis will be tested in three Specific Aims:
Aim 1 will test the hypothesis that the NLRP3 inflammasome, stimulated by increased H2O2 and increased mTORC1, mediates innate and adaptive immune responses in the SS following an elevation of sodium intake and results in the infiltration of activated T-lymphocytes into the kidney which amplify salt-sensitive hypertension and renal damage.
Aim 2 will test the hypothesis that elevated renal perfusion pressure increases intrarenal H2O2 and mTORC1 which serve to stimulate the NLRP3 inflammasome and T-cell infiltration in the SS kidney when fed high salt.
Aim 3 will test the hypothesis that T-cell infiltration into the kidney enhances H2O2 production and inflammasome activation which amplifies hypertension by decreasing GFR and increasing sodium reabsorption to further alter pressure natriuresis resulting in malignant hypertension. This proposal, which is addressing a significant health problem, is conceptually and technically innovative, utilizes a set of unique experimental approaches, and is highly dependent upon the expertise provided by the other investigators in Projects 1 and 2 and Cores A, B, and C of this PPG.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL116264-06
Application #
9417468
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
Kumar, Vikash; Wollner, Clayton; Kurth, Theresa et al. (2017) Inhibition of Mammalian Target of Rapamycin Complex 1 Attenuates Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats. Hypertension 70:813-821
Mattson, David L; Liang, Mingyu (2017) Hypertension: From GWAS to functional genomics-based precision medicine. Nat Rev Nephrol 13:195-196
Abais-Battad, Justine M; Dasinger, John Henry; Fehrenbach, Daniel J et al. (2017) Novel adaptive and innate immunity targets in hypertension. Pharmacol Res 120:109-115
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
Hashmat, Shireen; Rudemiller, Nathan; Lund, Hayley et al. (2016) Interleukin-6 inhibition attenuates hypertension and associated renal damage in Dahl salt-sensitive rats. Am J Physiol Renal Physiol 311:F555-61
Cowley Jr, Allen W; Yang, Chun; Zheleznova, Nadezhda N et al. (2016) Evidence of the Importance of Nox4 in Production of Hypertension in Dahl Salt-Sensitive Rats. Hypertension 67:440-50
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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