Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
Department of Endocrinology, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
Am J Physiol Renal Physiol. 2020 Mar 1;318(3):F576-F588. doi: 10.1152/ajprenal.00477.2019. Epub 2020 Jan 21.
Nephrotoxicity is a known clinical complication of cisplatin that limits the use of this potent antitumor drug. Cyclic nucleotide phosphodiesterases (PDEs) play complex roles in physiology and pathology. PDE4, which is a member of the PDE family, has four subtypes (PDE4A-PDE4D), and PDE4B plays an important role in inflammation. Thus, in the present study, we investigated the effect of PDE4/PDE4B inhibition on renal function and inflammation in a cisplatin nephrotoxicity model. In mice, cisplatin enhanced mRNA and protein expression of PDE4B in renal tubules. After treatment with the PDE4 inhibitor cilomilast, cisplatin-induced renal dysfunction, renal tubular injury, tubular cell apoptosis, and inflammation were all improved. Next, after silencing PDE4B in vivo, we observed a protective effect against cisplatin nephrotoxicity similar to that of the PDE4 inhibitor. In vitro, cisplatin-induced renal tubular cell death was strikingly ameliorated by the PDE4 inhibitor and knockdown along with the blockade of the inflammatory response. Considering the known roles of some cell survival pathways in antagonizing insults, we examined levels of PDE4-associated proteins sirtuin 1, phosphatidylinositol 3-kinase, and phosphorylated AKT in cisplatin-treated renal tubular cells with or without cilomilast treatment. Strikingly, cisplatin treatment downregulated the expression of the above proteins, and this effect was largely abolished by the PDE4 inhibitor. Together, these findings indicate the beneficial role of PDE4/PDE4B inhibition in treating cisplatin nephrotoxicity, possibly through antagonizing inflammation and restoring cell survival signaling pathways.
肾毒性是顺铂的已知临床并发症，限制了这种强效抗肿瘤药物的使用。环核苷酸磷酸二酯酶（PDEs）在生理和病理中发挥着复杂的作用。PDE4 是 PDE 家族的成员之一，有四个亚型（PDE4A-PDE4D），PDE4B 在炎症中起重要作用。因此，在本研究中，我们研究了 PDE4/PDE4B 抑制对顺铂肾毒性模型中肾功能和炎症的影响。在小鼠中，顺铂增强了肾小管中 PDE4B 的 mRNA 和蛋白表达。用 PDE4 抑制剂西洛司特治疗后，顺铂诱导的肾功能障碍、肾小管损伤、肾小管细胞凋亡和炎症均得到改善。接下来，在体内沉默 PDE4B 后，我们观察到与 PDE4 抑制剂相似的对顺铂肾毒性的保护作用。在体外，PDE4 抑制剂和沉默显著改善了顺铂诱导的肾小管细胞死亡，并阻断了炎症反应。考虑到一些细胞存活途径在对抗损伤方面的已知作用，我们检查了顺铂处理的肾小管细胞中与 PDE4 相关的蛋白 Sirtuin 1、磷酸肌醇 3-激酶和磷酸化 AKT 的水平，无论是否用西洛司特处理。引人注目的是，顺铂处理下调了上述蛋白的表达，而这种作用被 PDE4 抑制剂大大消除。综上所述，这些发现表明 PDE4/PDE4B 抑制在治疗顺铂肾毒性中的有益作用，可能通过拮抗炎症和恢复细胞存活信号通路。
