Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University; Changsha 410011, China.
Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University; Changsha 410011, China.
Toxicol Appl Pharmacol. 2021 May 1;418:115492. doi: 10.1016/j.taap.2021.115492. Epub 2021 Mar 17.
Cisplatin is a commonly used anti-cancer drug, but it induces nephrotoxicity. As a water-soluble vitamin B family member, nicotinamide (NAM) was recently demonstrated to have beneficial effects for renal injury, but its underlying mechanism remains largely unclear. Here, we suggest that NAM may exert protective effects against cisplatin-induced acute kidney injury (AKI) mainly via suppressing the poly ADP-ribose polymerase 1 (PARP1)/p53 pathway. In our experiment, NAM protected against cisplatin-induced apoptosis both in cultured renal proximal tubular cells and AKI in mice. Mechanistically, NAM suppressed the expression and activation of p53, a known mediator of cisplatin-induced AKI. Upstream of p53, NAM attenuated the induction of γ-H2AX, a hallmark of DNA damage response. Interestingly, PARP1 was activated in cisplatin AKI and this activation was inhibited by NAM. Pharmacological inhibition of PARP1 with PJ34 significantly ameliorated p53 activation and cisplatin-induced cell death in RPTCs and AKI in mice. Thus, NAM may protect against cisplatin-induced AKI by suppressing the PARP1/p53 pathway.
顺铂是一种常用的抗癌药物，但它会引起肾毒性。烟酰胺（NAM）作为一种水溶性维生素 B 族成员，最近被证明对肾损伤具有有益作用，但其潜在机制在很大程度上仍不清楚。在这里，我们提出 NAM 可能通过抑制聚 ADP-核糖聚合酶 1（PARP1）/p53 途径来发挥对顺铂诱导的急性肾损伤（AKI）的保护作用。在我们的实验中，NAM 可防止顺铂诱导的培养的肾近端小管细胞凋亡和 AKI 小鼠的肾损伤。在机制上，NAM 抑制了 p53 的表达和激活，p53 是顺铂诱导 AKI 的已知介质。在 p53 的上游，NAM 减弱了 γ-H2AX 的诱导，γ-H2AX 是 DNA 损伤反应的标志。有趣的是，PARP1 在顺铂 AKI 中被激活，而 NAM 抑制了 PARP1 的激活。用 PJ34 抑制 PARP1 的药理学抑制作用可显著改善 RPTC 中的 p53 激活和顺铂诱导的细胞死亡以及 AKI 小鼠中的 p53 激活和顺铂诱导的细胞死亡。因此，NAM 可能通过抑制 PARP1/p53 途径来防止顺铂诱导的 AKI。
