Early loss of glutathione ‐s‐ transferase (GST) activity during diverse forms of acute renal tubular injury

Abstract

Glutathione-S-transferases (GSTs) are a diverse group of phase II detoxification enzymes which primarily evoke tissue protection via glutathione conjugation to xenobiotics and reactive oxygen species. Given their cytoprotective properties, potential changes in GST expression during AKI has pathophysiologic relevance.Hence, we evaluated total GST activity, and the mRNA responses of nine cytosolic GST isotypes (GST alpha1, kappa1, mu1/5, omega1, pi1 sigma1, theta1, zeta1 mRNAs), in five diverse mouse models of AKI (glycerol, ischemia/reperfusion; maleate, cisplatin, endotoxemia). Excepting endotoxemia, each AKI model significantly reduced GST activity (~35%) during both the AKI "initiation" (0-4 h) and "maintenance" phases (18 or 72 h). During the AKI maintenance phase, increases in multiple GST mRNAs were observed. However, no improvement in GST activity resulted. Increased urinary GST excretion followed AKI induction.However, this could not explain the reduced renal GST activity given that it also fell in response to ex vivo renal ischemia (i.e., absent urinary excretion). GST alpha, a dominant proximal tubule GST isotype, manifested 5-10-fold protein increases following AKI, arguing against GST proteolysis as the reason for the GST activity declines. Free fatty acids (FFAs) and lysophospholipids, which markedly accumulate during AKI, are known to bind to, and suppress, GST activity. Supporting this concept, arachidonic acid addition to renal cortical protein extracts caused rapid GST activity reductions. Based on these results, we conclude that diverse forms of AKI significantly reduce GST activity. This occurs despite increased GST transcription/translation and independent of urinary GST excretion. Injury-induced generation of endogenous GST inhibitors, such as FFAs, appears to be a dominant cause.How to cite this article: Zager, R. A., & Johnson, A. C. M. (2022). Early loss of glutathione -stransferase (GST) activity during diverse forms of acute renal tubular injury. Physiological Reports,

Gut Microbiota and Neonatal Acute Kidney Injury

“…53,54 GST activity was reduced in different experimental models of AKI induced by glycerol, ischemia-reperfusion, maleate, cisplatin, and endotoxemia, indicating its pathophysiological significance in AKI. 54 Biomarkers of kidney tubular injury, including GST, precede sCr in diagnosing AKI in newborns. 55 A study with 113 very low birth weight infants showed that urinary GST levels in AKI patients were 3.7-fold higher than those in non-AKI patients.…”

“…GST consists of eight isomers, namely alpha, kappa, mu, omega, pi, sigma, theta, and zeta, 53 with the alpha and pi isomers located mainly in the proximal and distal convoluted tubules, respectively. 54 GST protects cells against reactive oxygen species by binding glutathione to electrophiles produced by cytochrome P450 metabolism, and the glutathione conjugates are finally excreted through bile or urine. 53,54 GST activity was reduced in different experimental models of AKI induced by glycerol, ischemia-reperfusion, maleate, cisplatin, and endotoxemia, indicating its pathophysiological significance in AKI.…”

“…54 GST protects cells against reactive oxygen species by binding glutathione to electrophiles produced by cytochrome P450 metabolism, and the glutathione conjugates are finally excreted through bile or urine. 53,54 GST activity was reduced in different experimental models of AKI induced by glycerol, ischemia-reperfusion, maleate, cisplatin, and endotoxemia, indicating its pathophysiological significance in AKI. 54 Biomarkers of kidney tubular injury, including GST, precede sCr in diagnosing AKI in newborns.…”

Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NAD+-Dependent Enzymes and Plant-Derived Natural Products

“…Targeting NAD + redox balance has been suggested as a strategy for fighting cisplatin-induced kidney injury [ 18 , 60 ]. Therefore, there has been an increasing interest in studying redox biochemistry and NAD + redox signaling in the pathogenesis of cisplatin renal toxicity [ 32 , 61 , 62 , 63 , 64 ]. The major NAD + -dependent redox enzymes that may be involved in cisplatin-induced kidney injury are shown in Figure 4 .…”