Obesity is associated with increased risk for diabetes and damage to the kidneys. Evidence suggests that miR-379 plays a role in the pathogenesis of diabetic kidney disease. However, its involvement in obesity-induced kidney injury is not known and was therefore investigated in this study by comparing renal phenotypes of high-fat diet (HFD)-fed wild-type (WT) and miR-379 knockout (KO) mice. Male and female WT mice on the HFD for 10 or 24 wk developed obesity, hyperinsulinemia, and kidney dysfunction manifested by albuminuria and glomerular injuries. However, these adverse alterations in HFD-fed WT mice were significantly ameliorated in HFD-fed miR-379 KO mice. HFD feeding increased glomerular expression of miR-379 and decreased its target gene, endoplasmic reticulum (ER) degradation enhancing α-mannosidase-like protein 3 (Edem3), a negative regulator of ER stress. Relative to the standard chow diet-fed controls, expression of profibrotic transforming growth factor-β1 (Tgf-β1) was significantly increased, whereas Zeb2, which encodes ZEB2, a negative regulator of Tgf-β1, was decreased in the glomeruli in HFD-fed WT mice. Notably, these changes as well as HFD-induced increased expression of other profibrotic genes, glomerular hypertrophy, and interstitial fibrosis in HFD-fed WT mice were attenuated in HFD-fed miR-379 KO mice. In cultured primary glomerular mouse mesangial cells (MMCs) isolated from WT mice, treatment with high insulin (mimicking hyperinsulinemia) increased miR-379 expression and decreased its target, Edem3. Moreover, insulin also upregulated Tgf-β1 and downregulated Zeb2 in WT MMCs, but these changes were significantly attenuated in MMCs from miR-379 KO mice. Together, these experiments revealed that miR-379 deletion protects mice from HFD- and hyperinsulinemia-induced kidney injury at least in part through reduced ER stress.NEW & NOTEWORTHY miR-379 knockout mice are protected from high-fat diet (HFD)-induced kidney damage through key miR-379 targets associated with ER stress (Edem3). Mechanistically, treatment of mesangial cells with insulin (mimicking hyperinsulinemia) increased expression of miR-379, Tgf-β1, miR-200, and Chop and decreases Edem3. Furthermore, TGF-β1-induced fibrotic genes are attenuated by a GapmeR targeting miR-379. The results implicate a miR-379/EDEM3/ER stress/miR-200c/Zeb2 signaling pathway in HFD/obesity/insulin resistance-induced renal dysfunction. Targeting miR-379 with GapmeRs can aid in the treatment of obesity-induced kidney disease.
Keywords: GapmeRs; endoplasmic reticulum stress; hyperinsulinemia; kidney injury; microRNA-379.