Bunge Ameliorates Streptozotocin-Induced Diabetic Nephropathy in Mice by Modulating GAS5 and miR-21 Expression.

Diabetic nephropathy (DN) is one of the major chronic complications of diabetes. Podocyte injury has been identified as a factor in the progression of albuminuria in DN. Bunge (PDB), an important Chinese herbal medicine, has strong hyperglycemia- and hyperlipidemia-lowering qualities. However, its effects on DN are unknown. The present study investigated the effects of PDB and flavone, which are the main ingredients in PDB, on DN and the possible mechanism, with a particular focus on the contributions of the lncRNA growth arrest-specific 5 (GAS5) and microRNA-21 (miR-21). Our results showed that administration of PDB (100 mg/kg/d) and flavone (10 mg/kg/d) for 12 weeks significantly alleviated albuminuria and decreased serum creatinine in STZ-induced DN mice. Moreover, renal cell apoptosis was repressed and diabetes-induced pathological alterations were reversed. We also found a significant decrease in GAS5 and PPARα expression, while miR-21 expression was increased in diabetic kidneys and podocytes under high glucose (HG) conditions. Notably, PDB and flavone counteracted these alterations. Mechanistic investigations showed that both GAS5 and PPARα are specific targets of miR-21, and that GAS5 could compete with PPARα for miR-21 binding, alleviating PPARα inhibition. Finally, we confirmed that PDB and flavone treatment remarkably attenuated the altered levels of oxidative stress parameters in HG-exposed podocytes, as well as inflammatory cytokines and profibrogenic mediators in the serum and urine of STZ-induced DN mice, and in the supernate of HG-exposed podocytes. Moreover, the interaction between GAS5 and miR-21/PPARα was required during this process. The results indicated that PDB and flavone exert renal protective effects, at least in part, by regulating the GAS5 and miR-21/PPARα pathways, which is a promising therapeutic target for delaying the onset of DN.