Poly(ADP‐ribose) Polymerase‐1 Mediates Inflammation and Necrosis in Cisplatin Nephrotoxicity

Unlike the better characterized role of poly(ADP‐ribose) polymerase‐1 (PARP‐1) in ischemic acute renal injury, the role of PARP‐1 in toxic renal injury remains unclear. Here, we explored the role of PARP‐1 in cisplatin nephrotoxicity. PARP‐1 wild‐type (WT) and knockout (KO) male mice were sacrificed 3 and 5 days after cisplatin intraperitoneal injection (single dose of 20 mg/kg body wt). The cisplatin treatment induced PARP‐1 expression and activation, which was accompanied by the development of renal dysfunction. PARP‐1 KO mice showed a significant reduction in cisplatin‐induced renal dysfunction and tubular necrosis, but not apoptosis, compared to WT mice. Moreover, up‐regulation of pro‐inflammatory proteins (including intercellular adhesion molecule‐1, tumor necrosis factor‐α, and toll‐like receptor‐4) and infiltration of neutrophil and macrophage were abrogated in PARP‐1 KO mice after cisplatin treatment. In vitro , primary cultured proximal tubule cells derived from PARP‐1 KO mice were protected from cisplatin‐induced necrosis, determined by propidium iodide staining, but not apoptosis, determined by TUNEL staining. Taken together, our findings demonstrate that PARP‐1 deficiency provides protection against cisplatin nephrotoxicity via inhibition of proximal tubular necrosis and inflammation. Targeting PARP‐1 may offer a potential therapeutic strategy for cisplatin nephrotoxicity.