Cordycepin ameliorates high glucose-induced proliferation, inflammation, and extracellular matrix deposition in glomerular mesangial cells through Smad7-dependent manner

Diabetic nephropathy (DN) is one of the most common causes of end-stage renal disease. The extracellular matrix deposition is potent pathogenic factors of renal fibrosis and injury. Cordycepin (Cor), a natural nucleoside compound from Cordyceps militaris, has been demonstrated reno-protective properties. Nevertheless, the role and underlying mechanism of Cor in DN have not been studied extensively. This study aimed to investigate the renal protective effects and mechanism of Cor on diabetic mouse models and high glucose (HG) induced-mouse glomerular mesangial cells (GMCs). The results of the biochemical indicators indicated that Cor could ameliorate renal dysfunction, as evidenced by reductions in serum creatinine, blood urea nitrogen, and urinary protein. Histological evaluation further confirmed that Cor ameliorated renal pathological changes, including mesangial matrix expansion, glomerular basement membrane thickening, glomerulosclerosis, and fibrillar collagen deposition. Additionally, Cor alleviated cell proliferation and fibrosis induced by high glucose in GMCs. Mechanistically, Cor upregulated the expression of Smad7, suppressed TGF-β/Smad pathway activation and its downstream NOX4-mediated NLRP3 inflammasome. Furthermore, knockdown of Smad7 by shRNA transfection abrogated the inhibiting effects of Cor in high glucose-induced GMCs. These findings suggested that Cor represented a promising therapeutic candidate for mitigating renal damage in diabetic nephropathy. The underlying mechanism involved the enhancement of Smad7 expression, which in turn suppresses TGF-β/Smad signaling and NOX4-mediated NLRP3 inflammasome activation.