The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that include obesity, insulin resistance, dyslipidemia, and hypertension, and is characterized by substantial inflammation. Obesity plays a particularly central role in the pathomechanisms of MetS and raises the risk for chronic kidney disease by about 4-fold. Early renal dysfunction in MetS may be linked to direct impact on the renal microcirculation, but the nature and mechanisms of the renal effects of MetS have not been elucidated. Novel imaging techniques for studying renal microvessels (MV), and models that mimic human renal physiology and pathophysiology, now provide a unique opportunity to assess the effects of MetS on renal MV function and structure. The hypothesis underlying this proposal is that MetS elicits renal MV remodeling that is partly mediated by inflammation, and in which monocyte chemoattractant protein-1 (MCP-1) plays a pivotal role. We hypothesize that consequent loss of MV integrity interferes with compensatory mechanisms meant to protect the kidney from ischemic or other insults. The secondary hypothesis is that imaging techniques can resolve MV function and architecture to allow demonstration of the renal effects of MetS and exploration of its mechanisms. To test this hypothesis we will utilize obese swine, a unique large animal model with a naturally occurring constellation of features of the MetS, and a combination of powerful imaging techniques both in vivo and in vitro. Multi- detector computed tomography (MDCT) will quantify non-invasively renal perfusion and function, and correlate with blood oxygen level-dependent (BOLD) MRI studies of renal oxygenation and tubular function. Renal fat content and inflammatory infiltration will be assessed using novel MRI techniques. Renal MV will then be reconstructed in situ using micro-CT, and their architecture and integrity quantified using novel tools. Importantly, chronic blockade of MCP-1 will establish the role of inflammation and MCP-1 as a mechanism underlying the effects of MetS on the kidney. Three hypotheses will be tested by 3 specific aims: 1. MetS impairs renal MV function and integrity by inducing oxidative stress, inflammation, and MV remodeling, which are reversible upon a change of diet;2. MV remodeling interferes with adaptation to ischemic insult (acute or chronic renal artery obstruction);3. MCP-1 contributes to MetS-induced renal microvascular alterations. Developing adequate strategies for early identification, treatment, and prevention of MetS, present a major challenge for health care professionals, facing an epidemic of overweight and sedentary lifestyle. Elucidation of the mechanisms involved in early deleterious effects of MetS at the level of the renal microcirculation can greatly advance our understanding of the pathogenesis of kidney injury during the evolution of MetS in a manner potentially applicable to humans. Indeed, these studies may shed light into and have a substantial ramification for designing preventive and diagnostic measures for management of patients with MetS.

Public Health Relevance

The metabolic syndrome (MetS) is associated with substantial cardiovascular risk and kidney injury. The current proposal utilizes a unique animal model possessing many human-like attributes, and interventions mimicking clinical conditions, which would facilitate translation to humans. The capability of MetS to impair renal vascular function and aggravate ischemia during insults will be examined in vivo using cutting edge CT and MRI techniques, and complemented by in vitro imaging and molecular biology studies performed in tissue from the same animals, thereby allowing their correlation and definition of functional significance. Elucidation of the mechanisms involved in early deleterious effects of MetS at the level of the renal microcirculation can greatly advance our understanding of the pathogenesis of renal injury during the evolution of MetS preceding overt CKD. The research and clinical availability of CT and MRI provides a unique opportunity to study these alterations in a manner potentially applicable to humans. These studies may therefore shed light into and have a substantial ramification for designing preventive (e.g. targeting risk factors) and diagnostic (e.g. imaging) measures for management of patients with cardiovascular risk factors and MetS.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZRG1-SBIB-P (02))
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Rys-Sikora, Krystyna E
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Mayo Clinic, Rochester
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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
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 68:331-2
Eirin, Alfonso; Lerman, Amir; Lerman, Lilach O (2016) The Emerging Role of Mitochondrial Targeting in Kidney Disease. Handb Exp Pharmacol :
Eirin, Alfonso; Textor, Stephen C; Lerman, Lilach O (2016) Emerging concepts for patients with treatment-resistant hypertension. Trends Cardiovasc Med 26:700-706
Zhang, Xin; Gibson, Matthew E; Li, Zi-Lun et al. (2016) Autophagy Portends the Level of Cardiac Hypertrophy in Experimental Hypertensive Swine Model. Am J Hypertens 29:81-9
Ma, Shuangtao; Zhu, Xiang-Yang; Eirin, Alfonso et al. (2016) Perirenal Fat Promotes Renal Arterial Endothelial Dysfunction in Obese Swine through Tumor Necrosis Factor-α. J Urol 195:1152-9
Zhu, Xiang-Yang; Ma, Shuangtao; Eirin, Alfonso et al. (2016) Functional Plasticity of Adipose-Derived Stromal Cells During Development of Obesity. Stem Cells Transl Med 5:893-900
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
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
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

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