Involvement of miR-27a-3p in diabetic nephropathy via affecting renal fibrosis, mitochondrial dysfunction, and endoplasmic reticulum stress.

Abstract

Diabetic nephropathy (DN) is acknowledged as a serious chronic complication of diabetes mellitus. Nevertheless, its pathogenesis is complicated and unclear. Thus, in this study, the role of miR-27a-3p-prohibitin/TMBIM6 signaling axis in the progression of DN was elucidated. Type 2 diabetic db/db mice and high glucose (HG)-challenged HK-2 cells were used as in vivo and in vitro models. Our results showed that miR-27a-3p was upregulated and prohibitin or transmembrane BAX inhibitor motif containing 6 (TMBIM6) was downregulated in the kidney tissues of db/db mice and HG-treated HK-2 cells. Silencing miR-27a-3p enhanced the expression of prohibitin and TMBIM6 in the kidney tissues and HK-2 cells. Inhibition of miR-27a-3p improved functional injury, as evidenced by decreased blood glucose, urinary albumin, serum creatinine, and blood urea nitrogen levels. MiR-27a-3p silencing ameliorated renal fibrosis, reflected by reduced profibrogenic genes (e.g., transforming growth factor β1, fibronectin, collagen I and III, and α-smooth muscle actin). Furthermore, inhibition of miR-27a-3p relieved mitochondrial dysfunction in the kidney of db/db mice, including upregulation of mitochondrial membrane potential, complex I and III activities, adenosine triphosphate, and mitochondrial cytochrome C, as well as suppressing reactive oxygen species production. In addition, miR-27a-3p silencing attenuated endoplasmic reticulum (ER) stress, reflected by reduced expression of p-IRE1α, p-eIF2α, XBP1s, and CHOP. Mechanically, we identified prohibitin and TMBIM6 as direct targets of miR-27a-3p. Inhibition of miR-27a-3p protected HG-treated HK-2 cells from apoptosis, extracellular matrix accumulation, mitochondrial dysfunction, and ER stress by regulating prohibitin or TMBIM6. Taken together, we reveal that miR-27a-3p-prohibitin/TMBIM6 signaling axis regulates the progression of DN, which can be a potential therapeutic target.