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 #
5P01HL116264-09
Application #
10075950
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
Palygin, Oleg; Miller, Bradley S; Nishijima, Yoshinori et al. (2018) Endothelin receptor A and p66Shc regulate spontaneous Ca2+ oscillations in smooth muscle cells controlling renal arterial spontaneous motion. FASEB J :fj201800776RR
Wade, Brittany; Petrova, Galina; Mattson, David L (2018) Role of immune factors in angiotensin II-induced hypertension and renal damage in Dahl salt-sensitive rats. Am J Physiol Regul Integr Comp Physiol 314:R323-R333
Chuppa, Sandra; Liang, Mingyu; Liu, Pengyuan et al. (2018) MicroRNA-21 regulates peroxisome proliferator-activated receptor alpha, a molecular mechanism of cardiac pathology in Cardiorenal Syndrome Type 4. Kidney Int 93:375-389
Evans, Louise C; Dayton, Alex; Yang, Chun et al. (2018) Transcriptomic analysis reveals inflammatory and metabolic pathways that are regulated by renal perfusion pressure in the outer medulla of Dahl-S rats. Physiol Genomics 50:440-447
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

Showing the most recent 10 out of 48 publications