The diagnosis, evaluation, and treatment of renovascular hypertension (RVH) and renovascular disease continue to be a subject of intense debate. Clinical trials of renal revascularization indicate that significant improvement in blood pressure control and/or recovery of renal function are difficult to achieve or predict reliably, partly because the factors that render renal injury and RVH irreversible remain unclear. The lack of appropriate models and tools to assess the hemodynamic and functional impairment in the stenotic kidney, or the compensatory response of the contralateral kidney, is a major impediment to advancing this field. Furthermore, little is known about the mechanisms and intracellular signaling cascades that mediate irreversible renal remodeling, fibrosis, and RVH, and how they are modulated by concurrent atherosclerosis. The overall objective of this PPG application is to gain critical knowledge about the pathophysiology of RVH and renovascular disease that will advance the diagnosis and treatment of this disease. Specifically, we will attempt to resolve intrinsic renal pathophysiological mechanisms that lead to irreversible injury in the stenotic and contralateral kidneys, and thereby limit the benefits of revascularization to improve renal function and blood pressure in many patients. Our working hypothesis is that renovascular disease and RVH activate multiple pathways of hemodynamic perturbation, progressive renal injury, and fibrogenesis, which are modulated by oxidative stress and ischemia. These pathways are amplified by contralateral kidney injury and coexisting atherosclerosis, and can hinder renal and blood pressure recovery. Several factors will be investigated in the four interrelated projects that compose and contribute to the central theme of this PPG. The proposal will characterize the role and effect of stenotic and contra-lateral kidney damage on the response to percutaneous transluminal renal angioplasty or to medical treatment in swine RVH in Project 1. and the exacerbating effects of atherosclerosis on evolution of renal injury in Project 2. The time course and the correlation between morphologic alterations and cellular signaling will be explored in genetically modified mice in Project 3. while the relevance to humans of knowledge gained in animal models will ultimately be tested and confirmed in Project 4. These projects will apply novel physiological imaging tools to study singlekidney hemodynamics, function, and ischemia, and cutting edge molecular biology techniques to characterize renal injury, and will apply them to assess the potential of interventions including renal revascularization, antihypertensive drug therapy, or progenitor cells to preserve the kidney. Identification and modification of these pathways using novel tools to study regional circulation and its relationship to tissue injury will allow identification of hypertensive individuals at risk for irreversible kidney injury, and those most likely to benefit from therapeutic intervention to reverse those pathways.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Barouch, Winifred
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Mayo Clinic, Rochester
United States
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Saad, Ahmed; Dietz, Allan B; Herrmann, Sandra M S et al. (2017) Autologous Mesenchymal Stem Cells Increase Cortical Perfusion in Renovascular Disease. J Am Soc Nephrol 28:2777-2785
Wang, Wei; Saad, Ahmed; Herrmann, Sandra M et al. (2016) Changes in inflammatory biomarkers after renal revascularization in atherosclerotic renal artery stenosis. Nephrol Dial Transplant 31:1437-43
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
Kwon, Soon Hyo; Tang, Hui; Saad, Ahmed et al. (2016) Differential Expression of microRNAs in Urinary Extracellular Vesicles Obtained From Hypertensive Patients. Am J Kidney Dis 68:331-332
Saad, Ahmed; Zhu, Xiang-Yang; Herrmann, Sandra et al. (2016) Adipose-derived mesenchymal stem cells from patients with atherosclerotic renovascular disease have increased DNA damage and reduced angiogenesis that can be modified by hypoxia. Stem Cell Res Ther 7:128
Saad, Ahmed; Wang, Wei; Herrmann, Sandra M S et al. (2016) Atherosclerotic renal artery stenosis is associated with elevated cell cycle arrest markers related to reduced renal blood flow and postcontrast hypoxia. Nephrol Dial Transplant 31:1855-1863
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Saad, Ahmed; Herrmann, Sandra M; Textor, Stephen C (2015) Chronic renal ischemia in humans: can cell therapy repair the kidney in occlusive renovascular disease? Physiology (Bethesda) 30:175-82
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