1. Amlodipine alleviates cisplatin-induced nephrotoxicity in rats through gamma-glutamyl transpeptidase (GGT) enzyme inhibition, associated with regulation of Nrf2/HO-1, MAPK/NF-κB, and Bax/Bcl-2 signaling
- Author
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Amany A. Azouz, Amira M. Abo-Youssef, and Esraa Abdel-Nassir Abdel-Razek
- Subjects
0301 basic medicine ,Nrf2, Nuclear factor erythroid 2-related factor 2 ,Anti-oxidant defense ,Bcl-2, B-cell lymphoma 2 ,MAPK, Mitogen-activated protein kinase ,NOx, Total nitrate/nitrite ,Pharmaceutical Science ,Pharmacology ,medicine.disease_cause ,VCAM-1, vascular cell adhesion molecule-1 ,Anti-inflammatory response ,chemistry.chemical_compound ,0302 clinical medicine ,GGT, gamma-glutamyl transpeptidase ,Kidney ,NADPH oxidase ,TNF-α, Tumor necrosis factor-alpha ,biology ,Chemistry ,Keap1, Kelch-like ECH-associated protein 1 ,H & E, Hematoxylin and eosin ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Original Article ,NADPH, Nicotinamide adenine dinucleotide phosphate ,HO-1, Heme oxygenase-1 ,BUN, Blood urea nitrogen ,medicine.drug ,GGT inhibition ,CMC, Carboxymethyl cellulose ,NO, Nitric oxide ,Nephrotoxicity ,GSH, Reduced glutathione ,03 medical and health sciences ,medicine ,Amlodipine ,IL-6, Interleukin-6 ,Cisplatin nephrotoxicity ,MDA, Malondialdehyde ,ComputingMethodologies_COMPUTERGRAPHICS ,Cisplatin ,lcsh:RM1-950 ,NF-κB, Nuclear factor-kappa B ,Glutathione ,HGF, Hepatocyte growth factor ,Bax, Bcl-2-associated X protein ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Renal cell survival ,Apoptosis ,biology.protein ,Oxidative stress ,ROS, Reactive oxygen species - Abstract
Graphical abstract, Background The therapeutic utility of the effective chemotherapeutic agent cisplatin is hampered by its nephrotoxic effect. We aimed from the current study to examine the possible protective effects of amlodipine through gamma-glutamyl transpeptidase (GGT) enzyme inhibition against cisplatin nephrotoxicity. Methods Amlodipine (5 mg/kg, po) was administered to rats for 14 successive days. On the 10th day, nephrotoxicity was induced by a single dose of cisplatin (6.5 mg/kg, ip). On the last day, blood samples were collected for estimation of kidney function, while kidney samples were used for determination of GGT activity, oxidative stress, inflammatory, and apoptotic markers, along with histopathological evaluation. Results Amlodipine alleviated renal injury that was manifested by significantly diminished serum creatinine and blood urea nitrogen levels, compared to cisplatin group. Amlodipine inhibited GGT enzyme, which participates in the metabolism of extracellular glutathione (GSH) and platinum-GSH-conjugates to a reactive toxic thiol. Besides, amlodipine diminished mRNA expression of NADPH oxidase in the kidney, while enhanced the anti-oxidant defense by activating Nrf2/HO-1 signaling. Additionally, it showed marked anti-inflammatory response by reducing expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB), with subsequent down-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Moreover, amlodipine reduced Bax/Bcl-2 ratio and elevated hepatocyte growth factor (HGF), thus favoring renal cell survival. Conclusions Effective GGT inhibition by amlodipine associated with enhancement of anti-oxidant defense and suppression of inflammatory signaling and apoptosis support our suggestion that amlodipine could replace toxic GGT inhibitors in protection against cisplatin nephrotoxicity.
- Published
- 2020