Bingül İlknur, Kalayci Rivaze, Tekkeşin Merva Soluk, Olgac Vakur, Bekpinar Seldag, Uysal Mujdat
Department of Medical Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Department of Laboratory Animal Science Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
J Mol Histol. 2024 Dec 4;56(1):23. doi: 10.1007/s10735-024-10308-z.
Oxidative stress, inflammation and renin-angiotensin system (RAS) activation play an important role in the nephrotoxicity which is caused by the long-term use of the immunosuppressive drug cyclosporine (CsA). This study investigates whether chenodeoxycholic acid (CDCA), an endogenous farnesoid X receptor (FXR) agonist with antioxidant and anti-inflammatory effects, modulates CsA nephrotoxicity. CsA (25 mg/kg/day; s.c.) was administered to rats for 12 days. CDCA (20 mg/kg/day; i.p.) injection was started 3 days before CsA and continued for 15 days. CDCA improved renal damage and function in CsA-administered rats. Renal function markers in serum, renal histology, oxidative stress, inflammation and RAS components were determined in kidney. CDCA reduced CsA-induced renal increases in NADPH oxidase 4 and NADPH oxidase 2 mRNA expressions, oxidative stress and inflammation. CDCA elevated renal FXR, small heterodimer partner-1, hypoxia-inducible factor and vascular endothelial growth factor and nuclear factor erythroid 2-related factor mRNA expressions in CsA rats. It prevents renin angiotensin system activation by reducing angiotensin II (Ang-II) levels in serum and upregulating renal mRNA expressions of Ang II type-II receptor (AT2R) and angiotensin converting enzyme 2 (ACE2), but not AT1R and ACE in CsA rats. Our results indicate that CDCA may be a protective agent against CsA-nephrotoxicity by decreasing inflammation, oxidative stress and RAS activation via AT2R and ACE2 upregulations.
氧化应激、炎症和肾素-血管紧张素系统（RAS）激活在长期使用免疫抑制药物环孢素（CsA）所致的肾毒性中起重要作用。本研究调查了具有抗氧化和抗炎作用的内源性法尼醇X受体（FXR）激动剂鹅去氧胆酸（CDCA）是否能调节CsA肾毒性。将CsA（25mg/kg/天；皮下注射）给予大鼠12天。在CsA给药前3天开始腹腔注射CDCA（20mg/kg/天），并持续15天。CDCA改善了给予CsA大鼠的肾损伤和肾功能。测定了血清中的肾功能标志物、肾脏组织学、氧化应激、炎症和RAS成分。CDCA降低了CsA诱导的肾脏中NADPH氧化酶4和NADPH氧化酶2 mRNA表达、氧化应激和炎症的增加。CDCA提高了CsA大鼠肾脏中FXR、小异源二聚体伴侣-1、缺氧诱导因子和血管内皮生长因子以及核因子红细胞2相关因子的mRNA表达。它通过降低血清中血管紧张素II（Ang-II）水平并上调CsA大鼠中血管紧张素II 2型受体（AT2R）和血管紧张素转换酶2（ACE2）的肾脏mRNA表达来防止肾素血管紧张素系统激活，但不影响AT1R和ACE。我们的结果表明，CDCA可能通过上调AT2R和ACE2来减少炎症、氧化应激和RAS激活，从而成为一种抗CsA肾毒性的保护剂。
