Knockdown of transient receptor potential melastatin 2 reduces renal fibrosis and inflammation by blocking transforming growth factor-β1-activated JNK1 activation in diabetic mice

Background: Diabetic nephropathy is a major complication of diabetes. We explore the protective effect of TRPM2 knockdown on the progression of diabetic nephropathy. Methods: A type 2 diabetes animal model was established in C57BL/6N mice by long-term high-fat diet (HFD) feeding combined with a single injection of 100 mg/kg streptozotocin (STZ). Genetic knockdown of TRPM2 in mouse kidneys was accomplished by the intravenous injection via the tail vein of adeno-associated virus type 2 carrying TRPM2 shRNA. Results: Mice with HFD/STZ-induced diabetes exhibited kidney dysfunction, as demonstrated by increased blood creatinine and urea nitrogen levels, accompanied by glomerulus derangement, tubule damage and extracellular matrix deposition in the interstitium. The protein expression of TRPM2, transforming growth factor-β1 (TGF-β1), connective tissue growth factor, α-smooth muscles actin, fibronectin, collagen I and collagen III, and the mRNA expression and contents of inflammatory factors, including interleukin-1β, interleukin-6, interferon-α, tumour necrosis factor -α and monocyte chemotactic protein -1, were significantly elevated in the renal tissues of the HFD/STZ-induced diabetes group compared to those of the two control groups. Furthermore, fluorescent staining of TRPM2 was markedly increased in the renal tubular epithelial cells from diabetic mice. Knockdown of TRPM2 significantly attenuated HFD/STZ-induced renal inflammatory responses and fibrosis, which was accompanied by activation of TGF-β1-activated c-Jun N-terminal protein kinase-1 (JNK1) signalling. JNK1 inactivation reversed hyperglycaemia-induced fibrosis and inflammation in HK-2 cells. Conclusion: TRPM2 silencing significantly attenuated fibrosis and inflammation in the kidneys of mice with HFD/STZ-induced diabetes, which was largely achieved via the inhibition of TGF-β1-activated JNK1 activation.