Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-45, New Orleans, LA 70112, USA.
J Mol Neurosci. 2011 Jan;43(1):58-66. doi: 10.1007/s12031-010-9394-1. Epub 2010 Jun 1.
Cisplatin is widely used for cancer chemotherapy, but nephrotoxicity is a major dose-limiting side effect. Our recent studies in vitro have shown that pituitary adenylate cyclase-activating polypeptide (PACAP) ameliorated cisplatin nephrotoxicity and that the renoprotection with PACAP38 was mediated by the PAC(1) receptor and through the p53-dependent and -independent suppression of apoptosis of human renal proximal tubular epithelial cells. In the present studies, PACAP38 prevented the rise in blood urea nitrogen and serum creatinine in mice treated with cisplatin. Cisplatin-exposed mice treated with PACAP38 had relatively well-preserved tubular integrity, even when the treatment started 24 h after cisplatin exposure. PACAP38 also reduced plasma and kidney levels of tumor necrosis factor-α and restored collagen IV levels. The damage to mouse kidney tubules caused by cisplatin involved p53 accumulation and was partially reversed by treatment with PACAP38. PACAP38 ameliorates cisplatin-induced acute kidney injury even when treatment started 24 h after the onset of injury and increases tubular regeneration, which further facilitates restoration of kidney function in addition to its anti-apoptotic effects.
顺铂被广泛用于癌症化疗，但肾毒性是一个主要的剂量限制副作用。我们最近的体外研究表明，垂体腺苷酸环化酶激活肽（PACAP）改善了顺铂肾毒性，PACAP38 的肾保护作用是通过 PAC1 受体介导的，通过 p53 依赖和独立的抑制人肾近端肾小管上皮细胞凋亡来实现的。在本研究中，PACAP38 可防止顺铂处理的小鼠血尿素氮和血清肌酐的升高。用 PACAP38 处理的暴露于顺铂的小鼠，即使在顺铂暴露 24 小时后开始治疗，其管状完整性也相对较好地保留。PACAP38 还降低了血浆和肾脏中肿瘤坏死因子-α的水平，并恢复了胶原 IV 的水平。顺铂引起的小鼠肾小管损伤涉及 p53 积累，并用 PACAP38 治疗部分逆转。PACAP38 可改善顺铂诱导的急性肾损伤，即使在损伤发生后 24 小时开始治疗，并且增加管状再生，这除了其抗凋亡作用外，还进一步促进了肾功能的恢复。
