Xia Yang, Jiang Hongwei, Chen Jinwen, Xu Fang, Zhang Guoxiu, Zhang Dongshan
Department of Emergency Medicine, Second Xiangya Hospital, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, People's Republic of China.
Department of Endocrinology, First Affiliated Hospital of Henan University of Science and Technology, People's Republic of China.
Life Sci. 2023 May 1;320:121540. doi: 10.1016/j.lfs.2023.121540. Epub 2023 Mar 11.
Our previous studies reported that low-dose paclitaxel (Taxol) ameliorated renal fibrosis in the unilateral ureteral obstruction and remnant kidney models. However, the regulatory role of Taxol in diabetic kidney disease (DKD) is still unclear. Herein, we observed that low-dose Taxol attenuated high glucose-increased expression of fibronectin, collagen I and collagen IV in Boston University mouse proximal tubule cells. Mechanistically, Taxol suppressed the expression of homeodomain-interacting protein kinase 2 (HIPK2) via disrupting the binding of Smad3 to HIPK2 promoter region, and consequently inhibited the activation of p53. Besides, Taxol ameliorated RF in Streptozotocin mice and db/db-induced DKD via suppression of Smad3/HIPK2 axis as well as inactivation of p53. Altogether, these results suggest that Taxol can block Smad3-HIPK2/p53 axis, thereby attenuating the progression of DKD. Hence, Taxol is a promising therapeutic drug for DKD.
我们之前的研究报道，低剂量紫杉醇（泰素）可改善单侧输尿管梗阻和残余肾模型中的肾纤维化。然而，紫杉醇在糖尿病肾病（DKD）中的调节作用仍不清楚。在此，我们观察到低剂量紫杉醇可减弱波士顿大学小鼠近端肾小管细胞中高糖诱导的纤连蛋白、I型胶原和IV型胶原表达增加。机制上，紫杉醇通过破坏Smad3与HIPK2启动子区域的结合来抑制同源结构域相互作用蛋白激酶2（HIPK2）的表达，从而抑制p53的激活。此外，紫杉醇通过抑制Smad3/HIPK2轴以及使p53失活，改善链脲佐菌素小鼠和db/db诱导的DKD中的肾纤维化。总之，这些结果表明紫杉醇可阻断Smad3-HIPK2/p53轴，从而减弱DKD的进展。因此，紫杉醇是一种有前景的DKD治疗药物。
