# miRNA Mediated Cross-Talk in CRS4: The Role of the miR-21-5p/PPAR-Alpha Pathway

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $385,000

## Abstract

PROJECT SUMMARY/ABSTRACT:
Chronic kidney disease (CKD) puts patients at a greatly increased risk of cardiovascular
disease, in a condition termed Type 4 Cardiorenal Syndrome (CRS4). While a large amount of
clinical data on CKD patients has identified some risk factors, very little is known about the
mechanisms by which this condition develops. We have utilized the 5/6 nephrectomy (5/6 NX)
model in Sprague Dawley rats to study the development of cardiac dysfunction resulting from
declining kidney function in a controlled animal model. The goal of our work is to identifying
molecular mechanisms that are mediating dysfunction and target them therapeutically. Small
RNA sequencing of left ventricle tissue identified miR-21-5p as a microRNA that is upregulated
in response to 5/6 NX. MicroRNAs are a class of several hundred endogenously produced
small RNAs that are involved with post-transcriptional regulation of gene expression in the heart
and elsewhere. Systemic knockdown of miR-21 prevented cardiac hypertrophy and enhanced
cardiac function without improving renal function or reducing blood pressure. This data
suggests that suppression of miR-21-5p prevented pathology through pressure independent
mechanisms. Subsequent mRNA sequencing identified gene expression changes in pathways
relating to fatty acid oxidation, glycolysis, hypertrophic signaling, inflammation, immune function
and atherosclerosis in response to miR-21 knockdown, suggesting that miR-21-5p may be
targeting peroxisome proliferator-activated receptor alpha (PPAR. PPAR is miR-21 target in
humans and is involved with regulation of all of the above mentioned pathways. PPAR is well
known to be suppressed with cardiac pathology, however miR-21 targeting of PPARa has not
yet been reported in a model of cardiac disease. We hypothesize that miR-21-5p produced by
the 5/6Nx remnant kidney supplies the LV with a pathological amount of miR-21-5p, contributing
to cardiac remodeling and dysfunction, at least in part, through targeting PPAR. This proposal
will focus understanding the functional and pathological implications of that regulation. We will
also locate LV cell types and tissue regions in which miR-21 targeting of PPAR is occurs and
study the gene expression changes that result. A role for the miR-21-5p/PPAR pathway has
not been reported in CRS4, or any other cardiac pathology. The studies outlined in this proposal
are designed to characterize the upstream and downstream mechanisms of this pathway in the
5/6Nx model. The discovery of a direct role for circulating miR-21-5p in disease development
would be an innovative breakthrough in the field of microRNA research, expanding our
understanding of circulating miRNAs from markers of disease to mediators of disease. Further,
findings from the proposed study could help elucidate mechanisms that regulate cardiac
dysfunction in CRS4 and identify new therapeutic approaches for preventing or improving
cardiac dysfunction in CKD patients.

## Key facts

- **NIH application ID:** 9918443
- **Project number:** 5R01HL128332-05
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Alison J Kriegel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918443

## Citation

> US National Institutes of Health, RePORTER application 9918443, miRNA Mediated Cross-Talk in CRS4: The Role of the miR-21-5p/PPAR-Alpha Pathway (5R01HL128332-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9918443. Licensed CC0.

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