Experimental and human data indicate that infiltration of immune cells into the kidney is important in the development of hypertension and kidney disease. Preliminary data in this proposal indicate that infiltrating T cells in the kidney are activated, that they can serve as a source of elevated cytokines and AngII, and that adoptive transfer of the activated, infiltrating cells harvested from the kidney of diseased Dahl SS rats ca mediate disease in donor animals. Moreover, preliminary data from unique animal models developed for this application in which recombination activating gene 1 (Rag1) or CD247, two important genes in immune cell signaling have been genetically mutated in the Dahl SS genetic background, supports the concept that infiltrating T cells in the kidney can mediate hypertension and renal disease. Of particular note, genetic association studies indicate that CD247 is important in hypertension and kidney disease in humans. This unique translational aspect of the proposal emphasizes the important link between the experimental observations made in animals in this proposal and human disease. These novel data demonstrate the importance of infiltrating immune cells in the kidney in the development of salt-sensitive hypertension and renal damage. It is not known, however, what immune cell type(s) is/are important in the response or what factors mediate the hypertension and renal damage. We propose that the infiltrating cells, specifically T lymphocytes, exert deleterious actions by releasing vasoactive factors (cytokines and/or AngII) in the kidney to exaggerate the ongoing disease process. Experiments in this proposal will test the general hypothesis that CD247, a gene associated with human hypertension, affects hypertension and renal disease by altering T lymphocyte infiltration and activation in the kidney. As a corollary to this hypothesis, we propose that the infiltrating immune cells act by increasing intrarenal cytokines and AngII which affect kidney function. This hypothesis will be tested in three mechanistically-based, Specific Aims.
Aim 1 will test the hypothesis that CD247 mediates infiltration of T cells into the kidney in Dahl SS rats.
Aim 2 will test the hypothesis that infiltrating T cells produce proinflammatory cytokines (i.e. IL-6) and AngII in the kidney during salt-sensitive hypertension and kidney damage in Dahl SS rats.
Aim 3 will test the hypothesis that intrarenal IL-6 and AngII participate in the development of salt-sensitive hypertension and renal damage in the Dahl SS rat by altering renal function. These integrative aims will address this hypothesis using a comprehensive approach ranging from cellular and molecular mechanisms to whole animal physiology and pathophysiology and utilize animal models specifically developed for this proposal.

Public Health Relevance

Hypertension is a leading risk factor for cardiovascular and kidney disease in the US. Experimental and human data indicate that infiltration of immune cells into the kidney is important in the development of hypertension and kidney damage. It is not known, however, what infiltrating immune cells are important in the disease response or what factors released from these cells mediate the deleterious effects in the kidney. The proposed studies will advance the scientific field by utilizing unique animal models, novel experimental tools, and an integrative approach to demonstrate the specific immune cell types and the factors released from these cells that lead to the amplification of sodium-sensitive hypertension and the development of kidney damage. Results of this work should result in novel therapy for hypertension and kidney disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK096859-03
Application #
8730147
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rys-Sikora, Krystyna E
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Mattson, David L (2014) Infiltrating immune cells in the kidney in salt-sensitive hypertension and renal injury. Am J Physiol Renal Physiol 307:F499-508
Das, Satarupa; Mattson, David L (2014) Exogenous L-arginine attenuates the effects of angiotensin II on renal hemodynamics and the pressure natriuresis-diuresis relationship. Clin Exp Pharmacol Physiol 41:270-8
Rudemiller, Nathan; Lund, Hayley; Jacob, Howard J et al. (2014) CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney. Hypertension 63:559-64
Lakshmikanthan, Sribalaji; Zieba, Bartosz J; Ge, Zhi-Dong et al. (2014) Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure. Arterioscler Thromb Vasc Biol 34:1486-94
Mattson, David L; Lund, Hayley; Guo, Chuanling et al. (2013) Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage. Am J Physiol Regul Integr Comp Physiol 304:R407-14