| 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. |
