Optimal management of patients with renovascular hypertension (RVH) due to atherosclerotic renal artery stenosis (RAS) is a matter of considerable controversy. Our long-term goal is to identify signaling pathways responsible for the development of ischemic injury in the stenotic kidney and hypertensive injury in the contralateral kidney in the 2-kidney, 1-clip model of RVH. Our recent studies have underscored a critical role for MCP-1 (CCL2) and other members of the CC chemokine family in the development of chronic renal damage in murine RVH. CC chemokine expression plays a critical role in the progression of renal disease in patients with metabolic syndrome and diabetes (MetS-D), but less is known about their role in renovascular disease (RVD). Most studies have focused on chemokine generation by circulating inflammatory cells and tissue macrophages, although parenchymal cells can produce CC chemokines and thereby contribute to injury. The next logical step in our ongoing studies is to elucidate a critical role for CC chemokine signaling by renal parenchymal cells and infiltrating macrophages and other inflammatory cells in the progression of RVD and how this process is modulated by the presence of MetS-D. The central hypothesis underlying our ongoing studies is that CC chemokine signaling directs early events in macrophage influx and polarization, leading to chronic injury, and that chemokine generation by parenchymal cells may contribute to/amplify this process. Furthermore, macrophages play an important role in the development of chronic renal damage in the contralateral kidney, a process that depends on the presence of MetS-D, as suggested by our preliminary studies.
Our aims are to 1) test the hypothesis that CC chemokines play a critical role in mediating the development and progression of bilateral chronic renal injury in mice with MetS-D and RVH;2) test the hypothesis that progression of CKD in mice with MetS-D and RVH requires interaction of CC chemokine signaling through bone marrow derived macrophages and parenchymal cells;and 3) test the hypothesis that M1 polarization is necessary for initiation and progression of renal disease in MetS-D mice with RVH. The proposed studies will provide an essential foundation towards understanding a mechanistic role for macrophage polarization and CC chemokine generation in the development of chronic renal lesions in a novel mouse model of RVH with MetS-D.

Public Health Relevance

High blood pressure and diabetes are major causes of renal failure as well as heart attacks and stroke. High blood pressure and diabetes are both associated with local and systemic inflammation. Our goal is to determine how inflammation contributes to kidney disease in patients with hypertension and diabetes and to determine whether blocking inflammation can prevent chronic kidney disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Davidson, Wendy F
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Mayo Clinic, Rochester
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Kashyap, Sonu; Osman, Mazen; Ferguson, Christopher M et al. (2018) Ccl2 deficiency protects against chronic renal injury in murine renovascular hypertension. Sci Rep 8:8598
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