Acute kidney injury model established by systemic glutathione depletion in mice

Abstract

Glutathione (GSH) is one of the most extensively studied tripeptides. The roles for GSH in redox signaling, detoxification of xenobiotics and antioxidant defense have been investigated. A drug‐induced rhabdomyolysis mouse model was recently established in L‐buthionine‐(S,R)‐sulfoximine (BSO; a GSH synthesis inhibitor)‐treated normal mice by co‐administration of antibacterial drug and statin. In these models, mild kidney injury was observed in the BSO only‐treated mice. Therefore, in this study, we studied kidney injury in the GSH‐depleted mouse. BSO was intraperitoneally administered twice a day for 7 days to normal mice. The maximum level of plasma creatine phosphokinase (351 487 ± 53 815 U/L) was shown on day 8, and that of aspartate aminotransferase was shown on day 6. Increased levels of blood urea nitrogen, plasma creatinine, urinary kidney injury molecule‐1 and urinary creatinine were observed. An increase of mRNA expression level of renal lipocalin 2/neutrophil gelatinase‐associated lipocalin was observed. Degeneration and necrosis in the skeletal muscle and high concentrations of myoglobin (Mb) in blood (347‐203 925 ng/mL) and urine (2.5‐68 583 ng/mL) with large interindividual variability were shown from day 5 of BSO administration. Mb‐stained regions in the renal tubule and renal cast were histologically observed. In this study, the GSH‐depletion treatment established an acute kidney injury mouse model due to Mb release from the damaged skeletal muscle. This mouse model would be useful for predicting potential acute kidney injury risks in non‐clinical drug development.

Chuan Huang Fang combining reduced glutathione in treating acute kidney injury (grades 1–2) on chronic kidney disease (stages 2–4): A multicenter randomized controlled clinical trial

“…The maintenance of hemodynamic stability needs to be given extensive consideration in AKI because of the impaired autoregulation mechanisms that are present ( Ostermann et al, 2019 ). As previously stated, RG has the potential to attenuate the damaging peroxide metabolites, decrease oxidative stress, and perform specific metabolic functions in the production of inflammatory components ( Matsubara et al, 2019 ; Zhang and Bai, 2019 ; Wang and Wu, 2021 ).…”

“…Our previously single-center clinical studies indicated Chuan Huang Fang (CHF) might have nephroprotection in A on C patients via mechanisms of reducing oxidative damage and decreasing inflammatory reactions ( Gong et al, 2014 ; Gong et al, 2020 ; Gong et al, 2021 ). Reduced glutathione (RG) has been shown to be beneficial in controlling local inflammation, reducing accumulation of reactive oxygen species, decreasing inflammatory markers, and lowering oxidative stress in the tissues and organs ( Matsubara et al, 2019 ; Zhang and Bai, 2019 ; Wang and Wu, 2021 ). Recently, it has been ascertained that RG could increase the therapeutic efficacy of high-flux hemodialysis among patients with severe AKI ( Hu, 2015 ; Yang et al, 2020 ).…”

Efficacy and Safety of Chuan Huang Fang Combining Reduced Glutathione in Treating Acute Kidney Injury (Grades 1–2) on Chronic Kidney Disease (Stages 2–4): Study Protocol for a Multicenter Randomized Controlled Clinical Trial

“…In consideration of autoregulation mechanisms damaged in AKI, maintaining hemodynamic stabilization should be attached great significance to [ 49 ]. As stated above, RG could clear away the harmful peroxide metabolites, restrain oxidative stress, and play certain metabolic roles in inflammatory factors [ 29 – 31 ].…”

“…In the process of AKI, numerous oxygen-free radicals are generated, endogenous antioxidants are constantly consumed, and large numbers of inflammatory factors are released, aggravating kidney injury [ 28 ]. Reduced glutathione (RG) can effectively control the local inflammatory response, reduce the accumulation of reactive oxygen species in renal tissues, lower the level of inflammatory factors, and relieve oxidative stress in organs and tissues [ 29 – 31 ]. Recently, RG is reported to improve the clinical efficacy of HFHD in patients with severe AKI [ 32 , 33 ].…”

Urinary Sulfate, Kidney Failure, and Death in CKD: The African American Study of Kidney Disease and Hypertension

“…Glutathione is a powerful antioxidant whose activity decreases with protein restriction. Lower glutathione levels are associated with greater reperfusion injury in AKI in animal models and humans (32)(33)(34), and glutathione suppresses prostaglandin synthesis pathways (35,36). In addition, glutathione plays a role in regulating cholesterol.…”