The renin-angiotensin system (RAS) plays a key role in the pathogenesis of chronic kidney injury. Clinical trials with RAS inhibitors suggest angiotensin II (Ang II) may promote renal injury through blood pressure- independent effects. Activation of the immune system by the RAS has been suggested as one mechanism mediating these actions. We have found that chronic infusion of Ang II causes significant kidney injury, infiltration of CD4+ T helper lymphocytes into the kidney, and enhanced expression of pro-inflammatory cytokines including interferon-g (IFN-g) and tumor necrosis factor-a (TNF-a). Administration of the broadly acting immunosuppressive agent mycyophenolate mofetil (MMF) abrogated these effects without affecting blood pressure. Accordingly, we hypothesize that activation of a CD4+ T cell-dependent cellular immune response by Ang II contributes to chronic kidney damage in this setting. Typically, CD4+ T cells do not directly mediate cytotoxic tissue injury. Rather, they regulate immune responses by differentiating into type 1 (Th1) or type 2 (Th2) CD4+ T helper cells. Whereas Th2 cells regulate antibody responses, Th1 cells secrete IFN-g leading to activation of macrophages and cytotoxic CD8+ T cells to mediate cellular damage. Activated macrophages in turn produce TNF-a, which further stimulates Th1 cells. We therefore suggest that Ang II acting through type I angiotensin (AT1) receptors promotes the development of a Th1 immune response in the kidney, with enhanced production of IFN-g and TNF-a leading directly to progressive kidney disease through blood pressure-independent mechanisms. To test this, we will examine Ang II-induced kidney injury in mouse lines with genetic modifications impacting: transcription factors critical for Th1 differentiation, key Th1 cytokines, and AT1 receptor responses in key cell lineages. In addition to CD4+ T cells, IFN-g and TNF-a are expressed by several immune cell lineages and even by renal parenchymal cells. Therefore, we have designed experiments to identify the cellular sources of these cytokines in Ang II- dependent kidney injury. Understanding how Th1 immune responses influence Ang II-induced renal damage should lead to more effective strategies for preventing progressive chronic kidney disease.

Public Health Relevance

Hypertension is a common cause of chronic kidney disease. This proposal explores how activation of a subset of T lymphocytes (Th1 cells) leads to kidney injury in angiotensin II-dependent hypertension. Understanding how Th1 immune responses influence angiotensin II-induced renal damage should lead to more effective strategies for preventing progressive chronic kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK087893-02
Application #
8081778
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Flessner, Michael Francis
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$322,517
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Rucker, A Justin; Rudemiller, Nathan P; Crowley, Steven D (2017) Salt, Hypertension, and Immunity. Annu Rev Physiol :
Rudemiller, Nathan P; Crowley, Steven D (2017) The role of chemokines in hypertension and consequent target organ damage. Pharmacol Res 119:404-411
Wu, Min; Zhang, Jian-Dong; Tang, Ri-Ning et al. (2017) Elevated PTH induces endothelial-to-chondrogenic transition in aortic endothelial cells. Am J Physiol Renal Physiol 312:F436-F444
Crowley, Steven D; Rudemiller, Nathan P (2017) Immunologic Effects of the Renin-Angiotensin System. J Am Soc Nephrol 28:1350-1361
Wen, Yi; Crowley, Steven D (2017) Renal effects of cytokines in hypertension. Curr Opin Nephrol Hypertens :
Justin Rucker, A; Crowley, Steven D (2017) The role of macrophages in hypertension and its complications. Pflugers Arch 469:419-430
Zhang, Jiandong; Rudemiller, Nathan P; Patel, Mehul B et al. (2016) Interleukin-1 Receptor Activation Potentiates Salt Reabsorption in Angiotensin II-Induced Hypertension via the NKCC2 Co-transporter in the Nephron. Cell Metab 23:360-8
Madan, Babita; Patel, Mehul B; Zhang, Jiandong et al. (2016) Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis. Kidney Int 89:1062-1074
Rudemiller, Nathan P; Crowley, Steven D (2016) Interactions Between the Immune and the Renin-Angiotensin Systems in Hypertension. Hypertension 68:289-96
Crowley, Steven D; Jeffs, Alexander D (2016) Targeting cytokine signaling in salt-sensitive hypertension. Am J Physiol Renal Physiol 311:F1153-F1158

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