Although atherosclerotic cardiovascular disease (CVD) is 10-20-fold higher in patients with chronic kidney damage (CKD) than in the general population, our understanding of the underlying mechanisms remains very limited. Notably, CKD is an angiotensin II (AII)-responsive state where targeting AII actions constitutes the cornerstone of medical therapy for a whole range of progressive renal injuries. Atherosclerotic CVD has also been found to be AII responsive in epidemiological studies and experimental models. The proposed studies will evaluate the pathophysiologic and therapeutic implications of interactions between renal dysfunction and AII in promoting atherosclerosis, testing the hypothesis that the macrophage AII type 1 receptor (AT1R) channels proatherogenic mechanisms in this setting. We will use atherosclerosis-prone mice and induce early or moderate CKD. We will use mice deficient in AT1R as bone marrow donors to create chimeric mice with AT1R-deficient infiltrating cells, but intact AT1R on resident vascular cells. We can then evaluate mechanisms of AII effects on macrophages, vascular cells and matrix interactions in the setting of CKD. Our central hypothesis will be tested by the following Specific Aims: I. Define the contribution and mechanisms by which the macrophage AT1R modulates cellular processes involved in CKD-induced acceleration of atherosclerosis. We hypothesize that macrophage AT1R promotes CKD-induced atherogenesis by increasing macrophage infiltration, inflammation, foam cell formation and proteolysis of extracellular matrix. II. Determine the role of modulators of the proatherogenic effects of macrophage AT1R in CKD-induced acceleration of atherosclerosis. We hypothesize that macrophage AT1R activates not only proatherogenic processes but also counterbalancing factors, including macrophage PPAR, which moderate the net vasculopathy.

Public Health Relevance

These studies will further our understanding of the leading cause of death and illness in patients with kidney disease, namely, atherosclerosis. The magnitude of the problem, especially in early kidney damage, has only recently been appreciated and is currently understudied. The proposed experiments will examine how the macrophage, a key inflammatory blood cell, makes the atherosclerosis worse in this setting and may give ideas for better treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087061-03
Application #
7799082
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Reid, Diane M
Project Start
2008-04-10
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$383,750
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Kon, Valentina; Yang, Haichun; Fazio, Sergio (2015) Residual Cardiovascular Risk in Chronic Kidney Disease: Role of High-density Lipoprotein. Arch Med Res 46:379-91
Kaseda, Ryohei; Jabs, Kathy; Hunley, Tracy E et al. (2015) Dysfunctional high-density lipoproteins in children with chronic kidney disease. Metabolism 64:263-73
Yamamoto, Suguru; Zhong, Jiayong; Yancey, Patricia G et al. (2015) Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype. Atherosclerosis 242:56-64
Prins, Petra A; Hill, Michael F; Airey, David et al. (2014) Angiotensin-induced abdominal aortic aneurysms in hypercholesterolemic mice: role of serum cholesterol and temporal effects of exposure. PLoS One 9:e84517
Yamamoto, Suguru; Kon, Valentina (2014) Chronic kidney disease induced dysfunction of high density lipoprotein. Clin Exp Nephrol 18:251-4
Yamamoto, Suguru; Yancey, Patricia G; Ikizler, T Alp et al. (2012) Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. J Am Coll Cardiol 60:2372-9
Zuo, Yiqin; Yang, Hai-Chun; Potthoff, Sebastian A et al. (2012) Protective effects of PPARýý agonist in acute nephrotic syndrome. Nephrol Dial Transplant 27:174-81
Ma, Li-Jun; Corsa, Bridgette A; Zhou, Jun et al. (2011) Angiotensin type 1 receptor modulates macrophage polarization and renal injury in obesity. Am J Physiol Renal Physiol 300:F1203-13
Sampson, Uchechukwu K; Perati, Prudhvidhar R; Prins, Petra A et al. (2011) Quantitative estimates of the variability of in vivo sonographic measurements of the mouse aorta for studies of abdominal aortic aneurysms and related arterial diseases. J Ultrasound Med 30:773-84
Yamamoto, Suguru; Zuo, Yiqin; Ma, Ji et al. (2011) Oral activated charcoal adsorbent (AST-120) ameliorates extent and instability of atherosclerosis accelerated by kidney disease in apolipoprotein E-deficient mice. Nephrol Dial Transplant 26:2491-7

Showing the most recent 10 out of 15 publications