Role of CC chemokine signaling in hyperglycemic renal artery stenosis

Project: Research project

Description

DESCRIPTION (provided by applicant): 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.
StatusFinished
Effective start/end date3/15/132/28/18

Funding

  • National Institutes of Health: $487,151.00
  • National Institutes of Health: $480,555.00
  • National Institutes of Health: $476,129.00
  • National Institutes of Health: $457,442.00

Fingerprint

CC Chemokines
Renal Artery Obstruction
Renovascular Hypertension
Kidney
Macrophages
Wounds and Injuries
Disease Progression
Chemokines
Metabolic Diseases
Surgical Instruments

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)