Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Peptides. 2010 Apr;31(4):592-602. doi: 10.1016/j.peptides.2009.12.018. Epub 2009 Dec 23.
Cisplatin nephrotoxicity involves DNA damage, proinflammatory responses and apoptosis/necrosis of renal proximal tubular epithelial cells. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to protect kidneys from ischemic injury and light chain-induced damage by modulating inflammation. Confluent monolayer of HK-2 human renal cells were exposed to 50 microM cisplatin in the presence or absence of either PACAP38 or p53 siRNA. Mice injected with cisplatin were also treated with PACAP38 daily for 3 days. The damage to HK-2 cells caused by cisplatin involved the activation of p53, caspase-7, and poly (ADP-ribose) polymerase-1 (PARP-1). PACAP38 prevented the decrease in the apurinic/apyrimidinic endonuclease-1 by suppressing p53 activation and blocked the cleavage of caspase-7 and PARP-1 in cisplatin-exposed cells. PACAP also markedly inhibited cisplatin-induced apoptotic tubule cell death. Exposure to cisplatin significantly suppressed the expression of fibronectin and collagens I and IV, and altered the integrin repertoire of human renal tubule cells, while PACAP partially reversed the reduction of fibronectin, collagen IV, and the integrin subunits in cells exposed to cisplatin. Experiments with PACAP receptor antagonists and siRNA silencing of p53 showed that the renoprotection with PACAP was mediated by the PAC(1) receptor and through both p53-dependent and -independent suppression of apoptosis. PACAP was renoprotective in vivo and prevented the rise in blood urea nitrogen and creatinine in mice treated with cisplatin. These results suggest that p53 plays a pivotal role in decreased integrin-mediated extracellular matrix component expression in cisplatin-induced tubule cell apoptosis, and reveal a novel aspect of PACAP-mediated renoprotection.
顺铂肾毒性涉及 DNA 损伤、促炎反应和肾近端小管上皮细胞的凋亡/坏死。已经表明，垂体腺苷酸环化酶激活肽 (PACAP) 通过调节炎症来保护肾脏免受缺血性损伤和轻链诱导的损伤。将 HK-2 人肾细胞的汇合单层暴露于存在或不存在 PACAP38 或 p53 siRNA 的 50 μM 顺铂中。用顺铂注射的小鼠也每天用 PACAP38 治疗 3 天。顺铂对 HK-2 细胞的损伤涉及 p53、半胱天冬酶-7 和聚（ADP-核糖）聚合酶-1 (PARP-1) 的激活。PACAP38 通过抑制 p53 激活来防止无嘌呤/无嘧啶内切酶-1 的减少，并阻止半胱天冬酶-7 和 PARP-1 在暴露于顺铂的细胞中的裂解。PACAP 还显着抑制顺铂诱导的肾小管细胞凋亡。暴露于顺铂会显着抑制纤连蛋白和 I 型和 IV 型胶原的表达，并改变人肾小管细胞的整合素谱，而 PACAP 部分逆转了暴露于顺铂的细胞中纤连蛋白、IV 型胶原和整合素亚基的减少。用 PACAP 受体拮抗剂和 p53 的 siRNA 沉默进行的实验表明，PACAP 的肾保护作用是通过 PAC(1)受体介导的，并且通过 p53 依赖性和非依赖性抑制凋亡来实现的。PACAP 在体内具有肾保护作用，并防止用顺铂治疗的小鼠血液尿素氮和肌酐的升高。这些结果表明，p53 在顺铂诱导的小管细胞凋亡中整合素介导的细胞外基质成分表达的减少中起关键作用，并揭示了 PACAP 介导的肾保护的一个新方面。
