Chitooligosaccharides ameliorate glomerular mesangial proliferation and inflammation in IgA nephropathy by blocking S1PR1/S1PR3 pathway

Immunoglobulin A nephropathy (IgAN) is a common primary glomerulonephritis characterized by metabolic abnormalities that accelerate disease progression. Chitooligosaccharides (COS) exhibit notable regulatory effects on metabolism and inflammation, yet their therapeutic effects and underlying mechanisms in IgAN remain unexplored. This study identified distinct serum metabolic profiles in IgAN patients, distinguishing them from healthy controls. Notably, a significant increase in the metabolite sphingosine-1-phosphate (S1P) not only indicated the severity of IgAN progression but also induced IgAN-like pathological phenotypes in glomerular mesangial cells (including excessive proliferation and inflammation). COS with specific degree of polymerization significantly inhibited the G2/M phase of the cell cycle in glomerular mesangial cells while promoting S-phase arrest and apoptosis (P < 0.05), collectively suppressing the excessive cellular proliferation induced by S1P. Additionally, COS reduced the levels of inflammatory factors including IL-6, IL-1β, TNF-α, and MCP-1 (P < 0.05) in both cell and animal models. Mechanistically, COS alleviated S1P-induced cellular effects and improved renal function and inflammation by suppressing the expression and activity of S1PR1 and S1PR3, which was similar with the effects of S1P antagonist FTY720. Overall, this study highlighted COS as a potential functional food for mitigating IgAN progression by targeting S1P signaling.