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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK073608-05
Application #
8129384
Study Section
Special Emphasis Panel (ZRG1-SBIB-P (02))
Program Officer
Rys-Sikora, Krystyna E
Project Start
2011-06-15
Project End
2016-05-31
Budget Start
2011-06-15
Budget End
2012-05-31
Support Year
5
Fiscal Year
2011
Total Cost
$394,250
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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