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EBioMedicine. 2018 Sep;35:260-269. doi: 10.1016/j.ebiom.2018.08.016. Epub 2018 Aug 14.

Tissue-specific effects of targeted mutation of Mir29b1 in rats.

Author information

1
Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College, Shanghai, PR China; Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: xuehong@fudan.edu.cn.
2
Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.
3
Departments of Medicine and Pharmacology, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
4
Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: mliang@mcw.edu.

Abstract

BACKGROUND:

miR-29 is a master regulator of extracellular matrix genes, but conflicting data on its anti-fibrotic effect have been reported. miR-29 improves nitric oxide (NO) production in arterioles by targeting Lypla1. Mir29b1 targeted mutation exacerbates hypertension in a model derived from the Dahl salt-sensitive rat. We examined the effect of Mir29b1 mutation on tissue fibrosis and NO levels with a focus on kidney regions.

METHODS:

Mir29b1 targeted mutant rats on the genetic background of SS-Chr13BN rats were studied. Masson trichrome staining, molecular and biochemical assays, metabolic cage studies, and bioinformatic analysis of human genomic data were performed.

FINDINGS:

The abundance of miR-29b and the co-transcribed miR-29a was substantially lower in mutant rats. Tissue fibrosis was significantly increased in the renal outer medulla, but not in the renal cortex, heart or liver in mutant rats on a 0.4% NaCl diet. Lypla1 protein abundance was significantly higher and NO levels lower in the renal outer medulla, but not in the renal cortex. After 14 days of a 4% NaCl diet, 24 h urine volume and urinary sodium excretion was significantly lower in mutant rats, and tissue fibrosis became higher in the heart. NO levels were lower in the renal outer medulla and heart, but not in the renal cortex. Human miR-29 genes are located in proximity with blood pressure-associated single nucleotide polymorphisms.

INTERPRETATION:

The renal outer medulla might be particularly susceptible to the injurious effects of a miR-29 insufficiency, which might contribute to the development of hypertension in Mir29b1 mutant rats.

KEYWORDS:

Fibrosis; Hypertension; Nitric oxide; Salt sensitive; miR-29

PMID:
30120082
PMCID:
PMC6156712
DOI:
10.1016/j.ebiom.2018.08.016
[Indexed for MEDLINE]
Free PMC Article

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