Probiotics-enhanced kynurenic acid mitigates cisplatin-induced nephrotoxicity in mice

Cisplatin chemotherapy is limited by dose-dependent nephrotoxicity. This study investigates the nephroprotective potential of kynurenic acid (KYNA), a tryptophan metabolite, against cisplatin-induced renal injury. Initial metabolic results revealed significant elevation of serum KYNA levels in cisplatin-treated mice, suggesting endogenous compensatory mechanisms. Systematic pharmacological evaluation demonstrated that intraperitoneal administration (i.p.) of KYNA (100, 250, and 500 mg/kg) dose-dependently attenuated cisplatin-induced nephrotoxicity through multi-modal mechanisms, including the suppression of pro-inflammatory cytokines via NF-κB p65 pathway inhibition and MAPKs dephosphorylation, reduction of renal apoptosis through Bcl-2 family rebalancing and caspase-3 cascade inhibition, and enhancement of antioxidant defenses via Nrf2 pathway activation with concomitant upregulation of downstream effectors. We further established that probiotic supplementation elevated endogenous KYNA production, achieving comparable renoprotection to high-dose KYNA monotherapy. Our findings delineate KYNA's multi-modal mechanisms against cisplatin nephrotoxicity and demonstrate that the probiotic-mediated modulation of host metabolism represents a viable strategy to enhance endogenous KYNA for renal protection.