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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI100911-05
Application #
9215631
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Davidson, Wendy F
Project Start
2013-03-15
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
5
Fiscal Year
2017
Total Cost
$473,874
Indirect Cost
$175,840
Name
Mayo Clinic, Rochester
Department
Type
Other Domestic Non-Profits
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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
Jiang, Kai; Ferguson, Christopher M; Ebrahimi, Behzad et al. (2017) Noninvasive Assessment of Renal Fibrosis with Magnetization Transfer MR Imaging: Validation and Evaluation in Murine Renal Artery Stenosis. Radiology 283:77-86
Kashyap, Sonu; Boyilla, Rajendra; Zaia, Paula J et al. (2016) Development of renal atrophy in murine 2 kidney 1 clip hypertension is strain independent. Res Vet Sci 107:171-7
Kashyap, Sonu; Warner, Gina M; Hartono, Stella P et al. (2016) Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension. Am J Physiol Renal Physiol 310:F372-84
Kashyap, Sonu; Engel, Sean; Osman, Mazen et al. (2016) Cardiovascular manifestations of renovascular hypertension in diabetic mice. PeerJ 4:e1736
Hartono, Stella P; Knudsen, Bruce E; Lerman, Lilach O et al. (2014) Combined effect of hyperfiltration and renin angiotensin system activation on development of chronic kidney disease in diabetic db/db mice. BMC Nephrol 15:58
Al-Suraih, Mohammed; Grande, Joseph Peter (2014) Management of renal artery stenosis: What does the experimental evidence tell us? World J Cardiol 6:855-60
Sterner, Rosalie M; Hartono, Stella P; Grande, Joseph P (2014) The Pathogenesis of Lupus Nephritis. J Clin Cell Immunol 5:
Hartono, Stella P; Knudsen, Bruce E; Zubair, Adeel S et al. (2013) Redox signaling is an early event in the pathogenesis of renovascular hypertension. Int J Mol Sci 14:18640-56
Ebrahimi, Behzad; Crane, John A; Knudsen, Bruce E et al. (2013) Evolution of cardiac and renal impairment detected by high-field cardiovascular magnetic resonance in mice with renal artery stenosis. J Cardiovasc Magn Reson 15:98

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