Nicotinamide Attenuates Complement and Coagulation Pathways and Resultant Renal Fibrosis

The coagulation and complement pathways interact with each other, promoting inflammation and increasing thrombotic risk. However, their roles in chronic kidney disease (CKD) remain unclear. In our CKD cohort, elevated plasma fibrinogen and shortened prothrombin time were associated with higher serum complement C3 and C4 levels. Moreover, gene expression analysis of CKD renal tissues in public databases showed a positive correlation between fibrinogen β chain and C3 expression levels. Finally, tissue factor (factor III), fibrinogen, and C3 deposition and the genes related to coagulation and complement cascades were upregulated in fibrotic kidneys of mice treated with adenine or folic acid. To explore the modulators of these systems, the therapeutic effects of nicotinamide (NAM), a NAD⁺ precursor with anti-inflammatory and antithrombotic properties, were investigated. KEGG pathway analysis with RNA sequencing identified a significant inhibition of coagulation and complement cascades by NAM administration in adenine-induced nephropathy. Moreover, NAM suppressed innate immune responses associated with the prothrombotic state, including inflammasome and neutrophil extracellular trap formation. Collectively, these results suggest that excessive coagulation and complement activities are involved in the pathogenesis of CKD and are modulated by NAM.