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Cited by 99Cardiac Fibrosis and RemodelingCardiovascular Function and Risk FactorsChronic Kidney Disease and Diabetes

MicroRNA-21 regulates peroxisome proliferator–activated receptor alpha, a molecular mechanism of cardiac pathology in Cardiorenal Syndrome Type 4

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Chuppa, Sandra, Liang, Mingyu, Liu, Pengyuan, Liu, Yong, Casati, Marc C., Cowley, Allen W., Patullo, Leah, Kriegel, Alison J.·2018·Kidney International
DOI 10.1016/j.kint.2017.05.014PMC PMC5787401
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Abstract

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.

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Cited by

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Authors
Chuppa, S., Liang, M., Liu, P., Liu, Y., Casati, M. C., Cowley, A. W., Patullo, L., & Kriegel, A. J.
Affiliations
Medical College of Wisconsin (US)
Corresponding author
Kriegel, Alison J.
ORCID
Venue
Kidney International
Publisher
Elsevier BV
Published
2018-02
Volume
93
Issue
2
Pages
375-389
ISSN
0085-2538 (ISSN-L)
DOI
10.1016/j.kint.2017.05.014
PMC
PMC5787401
OpenAlex
W2741023509
Cited by
99
References
4
Citations by year
2026: 7 · 2025: 11 · 2024: 8 · 2023: 11 · 2022: 19 · 2021: 10 · 2020: 14 · 2019: 14 · 2018: 5
FWCI
6.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Kidney International (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Heart Association (13SDG17100095)
  • National Institutes of Health (UL1TR000055, GM 066730, HL082798)
  • National Heart, Lung, and Blood Institute (P01HL082798, R01HL128332, P01HL116264, R01HL121233)
  • National Institute of General Medical Sciences (P01GM066730)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Keywords
miR-21-5p, PPARα, cardiorenal syndrome type 4, chronic kidney disease, left ventricular hypertrophy, 5/6 nephrectomy rat model, cardiac dysfunction, clofibrate, fatty acid metabolism, left ventricular dilatation, microRNA target regulation
MeSH terms
Animals, Clofibrate, Disease Models, Animal, Fatty Acids, Fibrosis, Gene Expression Regulation, Heart Ventricles, Male, Signal Transduction, Ventricular Function, Left, Rats, Sprague-Dawley, Hypertrophy, Left Ventricular, Ventricular Dysfunction, Left, Ventricular Remodeling, MicroRNAs, PPAR alpha, Cardio-Renal Syndrome

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