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miR-146b-5p has a sex-specific role in renal and cardiac pathology in a rat model of chronic kidney disease. Kidney Int 2019 12;96(6):1332-1345

Date

11/02/2019

Pubmed ID

31668631

Pubmed Central ID

PMC6941490

DOI

10.1016/j.kint.2019.07.017

Scopus ID

2-s2.0-85074541202   4 Citations

Abstract

Chronic kidney disease presents a complex and distinct pathological landscape in men and women, yet this difference is poorly understood. microRNAs are powerful molecular regulators of pathophysiology in the kidney and other organs. We previously reported a significant upregulation of miR-146b-5p in the 5/6 nephrectomy rat model of chronic kidney disease. Here we investigated the sex-specific contribution of miR-146b-5p to renocardiac pathology by generating a novel miR-146b-/- rat and characterized the expression of miR-146b-5p in both wild-type and knockout animals. The 5/6 nephrectomy or sham surgery was performed on rats of each genotype and sex. Renal pathology was examined through gross histology, plasma and urinary analysis of electrolytes and metabolites, and by chronic blood pressure monitoring. Cardiac pathology was monitored via echocardiography and pressure-volume analysis. The miR-146b-/- rats show functional knockout of miR-146b-5p in both the kidney and heart. While 5/6 nephrectomy induced tissue hypertrophy, miR-146b-/- female rats displayed exacerbated renal hypertrophy. Additionally, miR-146b-/- female rats exhibited a marked elevation of renal fibrosis and significant renal dysfunction yet lower blood pressure and less pronounced cardiac remodeling. These phenotypic differences were not exhibited in miR-146b-/- male rats. Ovariectomy ameliorated renal pathology and abolished genotypic differences. In vitro examination of transforming growth factor-β signaling in combination with miR-146b-5p manipulation supports a role for miR-146b-5p in mediating the protective benefit of estrogen from renal pathologies. Thus, our data highlight an important role of miR-146b-5p in modulating kidney disease progression and provide new avenues for the study of sex-specific pathology.

Author List

Paterson MR, Geurts AM, Kriegel AJ

Authors

Aron Geurts PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Alison J. Kriegel PhD Associate Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Line
Chick Embryo
Disease Models, Animal
Epithelial-Mesenchymal Transition
Female
Fibroblasts
Fibrosis
Hypertrophy
Kidney
Male
MicroRNAs
Myocardium
Ovariectomy
Rats, Sprague-Dawley
Renal Insufficiency, Chronic
Transforming Growth Factor beta
Ventricular Remodeling
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d