Higenamine hydrochloride prevents renal inflammation and fibrosis in diabetic nephropathy by inhibiting the STAT3 signaling pathway

Abstract

Higenamine Hydrochloride (HGN) is an alkaloid derived from the traditional Chinese medicinal herb Aconite, possesses pharmacological activities such as anti-inflammatory and antioxidant properties. Its specific role in diabetic nephropathy (DN) remains unknown. The purpose of this work was to investigate the protective impact of HGN against streptozotocin (STZ)-induced renal inflammation and fibrosis in DN mice, as well as to investigate its probable mechanism of action in vitro using high glucose (HG)-treated HK-2 cells. We constructed a mouse model of DN by intraperitoneal injection of STZ and a HK-2 cell model using HG treatment, followed by administration of HGN. Tissue distribution experiments, biochemical analysis, real-time PCR, immunoblotting, and histopathological examination were used to assess the effects of HGN on renal histopathology, inflammation, and fibrosis in DN mice and its molecular mechanisms. The results demonstrated that in the renal tissues of DN mice, HGN had the highest concentration. HGN treatment led to body weight increase, and blood glucose levels fell as well as the improvement in metabolic abnormalities. It further proved that HGN alleviated renal function damage by lowering serum creatinine (SCr), blood urea nitrogen (BUN), cystatin C (Cys-C), and renal index values. Moreover, HGN improved kidney histopathology, reduced renal tubular damage, and decreased interstitial inflammation. The kidneys had less collagen accumulation. At the same time, HGN decreased the expression of markers associated with inflammation (iNOS, IL-1β, IL-6, MCP-1) and fibrosis (Collagen-I, MMP9, α-SMA, CTGF). Mechanistic studies have shown that, in vitro, HGN inhibits STAT3 phosphorylation, thereby inhibiting the expression of inflammatory (iNOS, IL-1β, IL-6, and MCP-1) and fibrosis-related cytokines (Collagen-I, MMP9, α-SMA, and CTGF) in HK-2 cells under HG conditions. To summarize, HGN inhibits renal inflammation and fibrosis in DN mice by inhibiting the STAT3 pathway, and this discovery offers a new possible target for DN treatment.