RGD Reference Report - miR-146b-5p has a sex-specific role in renal and cardiac pathology in a rat model of chronic kidney disease. - Rat Genome Database

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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.

Authors: Paterson, Mark R  Geurts, Aron M  Kriegel, Alison J 
Citation: Paterson MR, etal., Kidney Int. 2019 Dec;96(6):1332-1345. doi: 10.1016/j.kint.2019.07.017. Epub 2019 Aug 16.
RGD ID: 127285407
Pubmed: PMID:31668631   (View Abstract at PubMed)
PMCID: PMC6941490   (View Article at PubMed Central)
DOI: DOI:10.1016/j.kint.2019.07.017   (Journal Full-text)

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.

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
renal fibrosis sexual_dimorphism IMPnephrectomy127285407; 127285407; 127285407 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Mir146b  (microRNA 146b)
Mir146bem1Mcwi  (microRNA 146b; CRISPR/Cas9 induced mutant 1, Mcwi)

SD-Mir146bem1Mcwi  (NA)

Additional Information