Hydrogen‐rich water alleviates cyclosporine A‐induced nephrotoxicity via the Keap1/Nrf2 signaling pathway

Abstract

Oxidative stress induced by long-term cyclosporine A (CsA) administration is a major cause of chronic nephrotoxicity, which is characterized by tubular atrophy, tubular cell apoptosis, and interstitial fibrosis in the progression of organ transplantation.Although hydrogen-rich water (HRW) has been used to prevent various oxidative stress-related diseases, its underlying mechanisms remain unclear. This study investigated the effects of HRW on CsA-induced nephrotoxicity and its potential mechanisms. After administration of CsA (25 mg/kg/day), rats were treated with or without HRW (12 mL/kg) for 4 weeks. Renal function and vascular activity were investigated. Histological changes in kidney tissues were analyzed using Masson's trichrome and terminal deoxynucleotidyl transferase dUTP nick-end labeling stains.Oxidative stress markers and the activation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway were also measured. We found that CsA increased the levels of reactive oxygen species (ROS) and malonaldehyde (MDA), but it reduced glutathione (GSH) and superoxide dismutase (SOD) levels. Such alterations induced vascular dysfunction, tubular atrophy, interstitial fibrosis, and tubular apoptosis. This was evident secondary to an increase in urinary protein, serum creatinine, and blood urea nitrogen, ultimately leading to renal dysfunction. Conversely, HRW decreased levels of ROS and MDA while increasing the activity of GSH and SOD. This was accompanied by an improvement in vascular and renal function. Moreover, HRW significantly decreased the level of Keap1 and increased the expression of Nrf2, NADPH dehydrogenase quinone 1, and heme oxygenase 1. In conclusion, HRW restored the balance of redox status, suppressed oxidative stress damage, and improved kidney function induced by CsA via activation of the Keap1/Nrf2 signaling pathway. K E Y W O R D S cyclosporine A, hydrogen-rich water, nephrotoxicity, oxidative stress

Hydrogen: A Novel Option in Human Disease Treatment

“…In 2011, Kamimura et al reported that prolonged consumption of HW significantly controlled fat and body weights in db/db obese mice by stimulating energy metabolism [ 152 ]. A recent study revealed that H 2 attenuated allergic inflammation in a mouse model of allergic airway inflammation by reversing an energy metabolic pathway switch from oxidative phosphorylation to aerobic glycolysis [ 153 ].…”

Lycium barbarum polysaccharides inhibit ischemia/reperfusion-induced myocardial injury via the Nrf2 antioxidant pathway

“…Growing evidences have shown that the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)-signal pathway plays crucial roles in oxidative stress related cardiovascular disease by regulating heme oxygenase 1 (HO1) and NADPH dehydrogenase quinone 1 (NQO1) [ 10 , 11 ]. Nrf2 is inhibited by binding with Keap1 in cytoplasm under physiological state.…”

Protective effects of molecular hydrogen on lung injury from lung transplantation

“…Meanwhile, HRS significantly decreased the protein expression of cytosolic Nrf2, while increased in the expression of nuclear Nrf2, but the total expression of Nrf2 did not increase in rats treated with. 59 These results indicated that hydrogen protects against oxidative stress injuries via the activation of the Keap1/Nrf2 signaling pathway.…”