Systemic immune responses play an increasingly recognized role in the pathogenesis of chronic kidney disease (CKD). Macrophages help to shape immune responses by differentiating into 2 functional phenotypes: M1 or M2 cells. M1 macrophages secrete pro-inflammatory cytokines and mediate tissue injury whereas M2 macrophages secrete anti-inflammatory cytokines and aid in tissue repair. Consistent with a role for M1 responses in mediating kidney damage, our preliminary studies using CKD models have revealed impressive infiltration of macrophages into the kidney coupled with enhanced renal expression of the M1 effector cytokines Interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a). We therefore hypothesize that M1 macrophages contribute to the progression of CKD through the actions of IL-1 and TNF-a. Mice doubly deficient for the IL-1 receptor (IL-1R) and TNF-receptor 1 (TNFR1) are unable to mount an M1 immune response (M1 KO). Accordingly, to directly test the contribution of the M1 response to CKD, we will measure parameters of kidney injury and fibrosis in M1 KO mice and controls following angiotensin II (Ang II)- dependent hypertension and unilateral ureteral obstruction (UUO). Potential regulators of M1/M2 macrophage differentiation include T lymphocyte subpopulations and type 1 angiotensin (AT1) receptors on macrophages. In this regard, pro-inflammatory Th1 T cells secrete IFN-g, driving macrophages toward the M1 phenotype, whereas in our preliminary studies activation of AT1 receptors directly on macrophages limits the expression of pro-inflammatory M1 cytokines both in the macrophage and the kidney and ameliorates renal damage. We therefore posit that in the setting of CKD, M1 macrophage responses are amplified by actions of Th1 cells but are inhibited by the activation of AT1 receptors on macrophages. We have already found that mice lacking Th1 responses (Tbet KO) have a blunted kidney injury response and muted renal expression of M1 cytokines in the setting of hypertension. Therefore, to determine the impact of Th1 T cells on M1 macrophage responses during renal fibrosis, we will examine kidney damage and M1/M2 macrophage differentiation in Tbet KO mice and controls following UUO. To examine the role of the macrophage AT1 receptor in limiting kidney damage mediated by M1 macrophages, we will further assess UUO- and hypertension-induced kidney injury and M1/M2 differentiation of macrophages in mice lacking the macrophage AT1 receptor (Macro KO) and controls. To define in vitro the mechanisms through which the macrophage AT1 receptor limits renal cell injury, we will co-culture wild-type and Macro KO macrophages with M1 KO, IL-1R KO, TNFR1 KO renal tubular cells and controls and then examine parameters of renal cell injury. We submit that activation of the AT1 receptor on macrophages will blunt the M1 macrophage response and in turn modify M1 cytokine signaling pathways to protect the kidney upon exposure to injurious stimuli. Examining these pathways should lead to more effective strategies for preventing progressive CKD.

Public Health Relevance

Cardiovascular disease is a prominent cause of mortality among veterans. Hypertension leads to a substantial burden of cardiovascular morbidity and chronic kidney disease in this population. Renal replacement therapies such as dialysis or renal transplantation are expensive modalities that are associated with significant morbidity and mortality. In providing a more precise understanding of the mechanisms underlying the progression of kidney damage during hypertension, the studies we propose should directly benefit the veteran's population by leading to more effective therapies for hypertensive kidney disease.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Nephrology (NEPH)
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Durham VA Medical Center
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Wen, Yi; Crowley, Steven D (2018) Renal effects of cytokines in hypertension. Curr Opin Nephrol Hypertens 27:70-76
Rucker, A Justin; Rudemiller, Nathan P; Crowley, Steven D (2018) Salt, Hypertension, and Immunity. Annu Rev Physiol 80:283-307
Justin Rucker, A; Crowley, Steven D (2017) The role of macrophages in hypertension and its complications. Pflugers Arch 469:419-430
Rudemiller, Nathan P; Crowley, Steven D (2017) The role of chemokines in hypertension and consequent target organ damage. Pharmacol Res 119:404-411
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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

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