Chenodeoxycholic acid alleviated the cyclosporine-induced nephrotoxicity by decreasing oxidative stress and suppressing renin-angiotensin system through AT2R and ACE2 mRNA upregulation in rats

• Published in: Journal of molecular histology 2025-02, Vol.56 (1), p.23, Article 23
• Main Authors: Bingül, İlknur, Kalayci, Rivaze, Tekkeşin, Merva Soluk, Olgac, Vakur, Bekpinar, Seldag, Uysal, Mujdat
• Format: Article
• Language: English
• Subjects: ACE2; Angiotensin AT1 receptors; Angiotensin AT2 receptors; Angiotensin II; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Cell Biology; Chenodeoxycholic acid; Chenodeoxycholic Acid - pharmacology; Cyclosporine; Cyclosporins; Developmental Biology; Endocrine system; Hypoxia-inducible factors; Immunosuppressive agents; Inflammation; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney Diseases - chemically induced; Kidney Diseases - drug therapy; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidney Diseases - prevention & control; Life Sciences; Male; mRNA; NAD(P)H oxidase; NADPH Oxidase 2 - genetics; NADPH Oxidase 2 - metabolism; NADPH Oxidase 4 - genetics; NADPH Oxidase 4 - metabolism; Original Paper; Oxidative stress; Oxidative Stress - drug effects; Peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - genetics; Peptidyl-Dipeptidase A - metabolism; Rats; Receptor, Angiotensin, Type 2 - genetics; Receptor, Angiotensin, Type 2 - metabolism; Renal function; Renin; Renin-Angiotensin System - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Up-regulation; Up-Regulation - drug effects; Vascular endothelial growth factor
• ISSN: 1567-2379; 1567-2387; 1567-2387
• 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.