PARP1 Deficiency Attenuates Cisplatin Nephrotoxicity and Renal COX-2/PGE2 Response.
Bhatti Theophilus T, Yu Jia-Bin JB, Bae Ji-Yeong JY, Kim Jinu J
Cisplatin is a widely used chemotherapeutic agent whose clinical utility is limited by nephrotoxicity, characterized by tubular injury and renal inflammation. Poly(ADP-ribose) polymerase 1 (PARP1) contributes to cisplatin-induced kidney injury and inflammatory signaling, but the downstream inflammatory pathways involved remain incompletely defined. Here, we investigated whether PARP1 modulates the renal cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) response during cisplatin-induced acute kidney injury (AKI). Female wild-type and Parp1-knockout (KO) mice on a C57BL/6 background received a single intraperitoneal injection of cisplatin (20 mg/kg) and were evaluated at days 1 and 4, while male mice were evaluated at day 4 for renal function. Renal function, tubular injury, inflammatory gene expression, NF-κB activation, Ptgs2 mRNA and COX-2 protein expression, and kidney PGE2 levels were assessed. Cisplatin markedly increased plasma creatinine and blood urea nitrogen levels and induced tubular injury in both the renal cortex and outer stripe of the outer medulla, whereas these changes were significantly attenuated in Parp1 KO mice at day 4. At day 4, cisplatin-induced renal expression of Il1b, Il6, Ccl5, Cxcl1, and Cxcl2 was also substantially reduced by Parp1 deficiency. Cisplatin increased renal NF-κB p65 activation, as assessed by the p-p65/t-p65 ratio, in wild-type mice, whereas this response was significantly attenuated in Parp1 KO mice. Consistently, cisplatin increased renal Ptgs2 mRNA expression, COX-2 protein abundance, and PGE2 levels in wild-type mice, whereas all three responses were significantly attenuated in Parp1 KO mice. In particular, the cisplatin-induced increase in renal PGE2 was nearly abolished in the absence of PARP1. These findings demonstrate that PARP1 deficiency attenuates cisplatin-induced renal dysfunction, tubular injury, and inflammatory responses and identify suppression of NF-κB activation and the COX-2/PGE2 response as features of this protective phenotype. The results support a potential PARP1-NF-κB-COX-2/PGE2 signaling axis in cisplatin nephrotoxicity.