Cardiovascular functional decline is worsened in patients and animals models with Chronic Kidney Disease (CKD) due to increased structural remodeling of cardiovascular tissues. Previous studies evaluating molecular mechanisms underlying these cardiovascular changes have revealed a central role for Na/K-ATPase (NKA) receptor complex activation in cardiac fibrosis. Signaling by the NKA receptor complex is induced by increased plasma levels of the cardiotonic steroid (CTS), Marinobufagenin (MBG). In accordance, inhibition of NKA signaling by Src or mammalian target of Rapamycin (mTOR) pathway inhibitors led to attenuation of cardiac fibrosis. However, these inhibitors also caused increased cardiac cell death when used in conjunction with elevated levels of CTS. Strategies to prevent fibrosis were then shifted to seek a more specific target that directly regulates fibrotic growth in the heart. Using heart tissue from 5/6th partial nephrectomized (PNx) or MBG-infused animals, data shows that PNx and MBG infusion significantly decreased microRNA 29b (miR29b) expression, which directly targets mRNA of collagen, an essential component for fibrosis. The role of miR29b in collagen synthesis and fibrosis in vitro has been well established. In animal models, significant down- regulation of miR-29b correlates with significantly increased collagen mRNA levels in cardiac tissues. Given the in vivo data and evidence from literature, it is hypothesized that miR29b is an important regulator of cardiac fibrosis with specific inhibitory effects on profibrotic signaling in cardiac cells and that miR29b mimics can be used as a potential in vivo therapeutic agents to prevent cardiac fibrosis induced by CKD. Specifically, in vitro it is aimed to test if over-expression of miR29b prevents collagen synthesis induced by MBG in cardiac fibroblasts and myocytes. In vivo, the aim is to test if chronic miR29b mimic infusion prevents cardiac fibrosis in the PNx model of CKD. Research has shown that PNx and MBG-infusion cause cardiac fibrosis and cardiomyopathy. Both increase plasma MBG-Levels, NKA-receptor complex signaling activation and decrease miR-29b expression in cardiac tissues. To determine whether exogenously increasing miR29b levels prevents cardiac fibrosis in the PNx model of CKD, rats subjected to PNx-surgery will be infused with either miR29b mimic or scramble miRNA through an osmotic minipump. Four weeks following PNx, rats will be sacrificed and the left ventricle evaluated for miR29b levels and physiological measures of cardiac fibrosis and left ventricular function. This study if successful will provide a novel therapeutic strategy for preventing CKD induced cardiovascular decline associated cardiac fibrosis, while also providing proof of concept approaches to utilizing miRNA mimics to treat diseases.

Public Health Relevance

Chronic diseases of one organ commonly have negative effects on other organs;chronic kidney disease for example is often complicated by decreasing heart health. A major cause of the decline in heart health is scar formation. This study will evaluate a novel small molecule that prevents the production of scars and has a lower potential for negative side effects than currently available treatments.

Agency
National Institute of Health (NIH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK104615-01
Application #
8836690
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Rankin, Tracy L
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Toledo
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Toledo
State
OH
Country
United States
Zip Code
43614
Yu, Mark Shipeng; Folt, David A; Drummond, Christopher A et al. (2014) Endovascular versus medical therapy for atherosclerotic renovascular disease. Curr Atheroscler Rep 16:459