CGS-21680 defers cisplatin-induced AKI-CKD transition in C57/BL6 mice

• Published in: Chemico-biological interactions 2024-11, Vol.403, p.111255, Article 111255
• Main Authors: Elbrolosy, Menna A., Helal, Manar G., Makled, Mirhan N.
• Format: Article
• Language: English
• Subjects: AKI-CKD transition; CGS-21680; Cisplatin; Fibrosis; Vasodilation
• ISSN: 0009-2797; 1872-7786; 1872-7786
• DOI: 10.1016/j.cbi.2024.111255

Acute kidney injury (AKI), with a high mortality and morbidity, is known as a risk factor for developing progressive chronic kidney disease (CKD). Targeting transition of AKI to CKD displays an excellent therapeutic potential. This study aims at investigating the role of CGS-21680, selective A2AR agonist, in deferring Cis-induced AKI-CKD transition. The AKI-CKD transition model was induced in C57/BL6 mice by repeated low doses of Cis (2.5 mg/kg i.p for 5 consecutive days in two cycles with a recovery phase of 16 days between two cycles). CGS-21680 was administered daily for 6 weeks (0.1 mg/kg, i.p). Urine, blood, and kidney were collected at three different time points to track the disease progression. CGS-21680 administration preserved kidney function and attenuated tubular damage as evidenced by hematoxylin-eosin (H&E) histopathology. CGS-21680 significantly restored oxidative status as reflected by reduced malondialdehyde (MDA) content and increased total antioxidant capacity (TAC). CGS-21680 showed anti-inflammatory effect as indicated by decreased TNF-α and iNOS. Additionally, CGS-21680 ameliorated endothelial dysfunction and enhanced renal vasodilation as evidenced by upregulation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) expression and down regulation of endothelin-1 (ET-1) and its receptor endothelin-A (ET-A) receptor expression. CGS-21680 also attenuated renal fibrosis as reflected by the reduction of percentage of fibrosis in Masson's trichome-stained renal sections and down regulation of transforming growth factor beta1 (TGF-β1) protein expression in IHC-stained renal sections. In conclusion, CGS-21680 could defer Cis-induced AKI-CKD transition via its vasodilatory, antioxidant, anti-inflammatory, and anti-fibrotic effects. Effect of CGS-21680 on Cis-induced AKI-CKD transitionCis administration resulted in elevation of renal ET-1 and ET-A receptor expression but not ET-B receptor expression. ET-A activation by ET-1 and downregulation of eNOS/NO expression leads to vasoconstriction and hypoxia. Hypoxia in turn induces oxidative stress and subsequently triggers inflammation as demonstrated by reduction of TAC and elevation of MDA, TNF-α, and iNOS. Oxidative stress and inflammation induce maladaptive repair and fibrosis progression as demonstrated by increased collagen deposition and TGF-β1 expression. CGS-21680 has the potential to improve renal blood flow and inhibit oxidative stress and inflammation through modulation of