Department of Nephrology and Rheumatology, Chinese Medicine Hospital of Hainan Province, Haikou, China.
Ren Fail. 2020 Nov;42(1):216-224. doi: 10.1080/0886022X.2020.1729188.
Nephrotoxicity is the main side effect of cyclosporine A and finding an effective combating method is urgent. The present study investigates the improving effect of erythropoietin (EPO) on cyclosporine A induce renal injury in rats and further explores its possible mechanism. Recombinant adenovirus for expression of EPO was constructed and injected into kidney with multipoint. Levels of blood urea nitrogen (BUN) and serum creatinine (SCr) were detected by kits. HE staining and Masson's trichrome staining were used to evaluate pathological changes. ELISA was performed to detect the levels of transforming growth factor (TGF)-β1, interleukin (IL)-1β, and IL-6 in serum. Levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in kidney were detected according to manufacturer's instruction. Western blotting was performed to observe the protein expression levels of peroxisome proliferator-activated receptor γ (PPAR γ), Toll-like receptor (TLR) 4, and TGF-β1. Results showed that EPO overexpression in rat kidney could significantly improve renal injury and fibrosis, suppress the release of inflammatory factors and reduce oxidative stress induced by cyclosporine A. Western blotting results showed that EPO overexpression could up-regulate the expression of PPARγ and down-regulate the expression of TLR4 and TGF-β1. Interestingly, when PPARγ activity was inhibited by T0070907, an effective and specific PPARγ inhibitor, the therapeutic effect of EPO was significantly attenuated. Taken together, above results shown the protective effect of EPO on cyclosporine A-induced renal injury and confirmed that EPO's anti-inflammation and antioxidative stress involving the PPAR γ/TLR4/TGFβ1 axis.
肾毒性是环孢素 A 的主要副作用，寻找有效的治疗方法迫在眉睫。本研究探讨了促红细胞生成素（EPO）对环孢素 A 诱导大鼠肾损伤的改善作用，并进一步探讨了其可能的机制。构建了表达 EPO 的重组腺病毒，多点注射到肾脏中。试剂盒检测血尿素氮（BUN）和血清肌酐（SCr）水平。HE 染色和 Masson 三色染色评估病理变化。ELISA 法检测血清转化生长因子（TGF）-β1、白细胞介素（IL）-1β和 IL-6水平。根据制造商的说明检测肾丙二醛（MDA）和超氧化物歧化酶（SOD）水平。Western blot 法观察过氧化物酶体增殖物激活受体 γ（PPAR γ）、Toll 样受体（TLR）4 和 TGF-β1 的蛋白表达水平。结果表明，EPO 在大鼠肾脏中的过表达可显著改善肾损伤和纤维化，抑制炎症因子的释放，减轻环孢素 A 诱导的氧化应激。Western blot 结果表明，EPO 过表达可上调 PPARγ的表达，下调 TLR4 和 TGF-β1 的表达。有趣的是，当 PPARγ 活性被有效的、特异性的 PPARγ抑制剂 T0070907 抑制时，EPO 的治疗效果明显减弱。综上所述，以上结果表明 EPO 对环孢素 A 诱导的肾损伤具有保护作用，并证实了 EPO 通过 PPAR γ/TLR4/TGFβ1 轴发挥抗炎和抗氧化应激作用。
