MicroRNA-21 regulates peroxisome proliferator-activated receptor alpha, a molecular mechanism of cardiac pathology in Cardiorenal Syndrome Type 4. Kidney Int 2018 Feb;93(2):375-389
Date
08/02/2017Pubmed ID
28760335Pubmed Central ID
PMC5787401DOI
10.1016/j.kint.2017.05.014Scopus ID
2-s2.0-85026463717 (requires institutional sign-in at Scopus site) 65 CitationsAbstract
Cardiovascular events are the leading cause of death in patients with chronic kidney disease (CKD), although the pathological mechanisms are poorly understood. Here we longitudinally characterized left ventricle pathology in a 5/6 nephrectomy rat model of CKD and identify novel molecular mediators. Next-generation sequencing of left ventricle mRNA and microRNA (miRNA) was performed at physiologically distinct points in disease progression, identifying alterations in genes in numerous immune, lipid metabolism, and inflammatory pathways, as well as several miRNAs. MiRNA miR-21-5p was increased in our dataset and has been reported to regulate many identified pathways. Suppression of miR-21-5p protected rats with 5/6 nephrectomy from developing left ventricle hypertrophy and improved left ventricle function. Next-generation mRNA sequencing revealed that miR-21-5p suppression altered gene expression in peroxisome proliferator-activated receptor alpha (PPARα) regulated pathways in the left ventricle. PPARα, a miR-21-5p target, is the primary PPAR isoform in the heart, importantly involved in regulating fatty acid metabolism. Therapeutic delivery of low-dose PPARα agonist (clofibrate) to rats with 5/6 nephrectomy improved cardiac function and prevented left ventricle dilation. Thus, comprehensive characterization of left ventricle molecular changes highlights the involvement of numerous signaling pathways not previously explored in CKD models and identified PPARα as a potential therapeutic target for CKD-related cardiac dysfunction.
Author List
Chuppa S, Liang M, Liu P, Liu Y, Casati MC, Cowley AW, Patullo L, Kriegel AJAuthor
Alison J. Kriegel PhD Associate Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCardio-Renal Syndrome
Clofibrate
Disease Models, Animal
Fatty Acids
Fibrosis
Gene Expression Regulation
Heart Ventricles
Hypertrophy, Left Ventricular
Male
MicroRNAs
PPAR alpha
Rats, Sprague-Dawley
Signal Transduction
Ventricular Dysfunction, Left
Ventricular Function, Left
Ventricular Remodeling
