Renal Glutathione: Dual roles as antioxidant protector and bioactivation promoter

The tripeptide glutathione (GSH) possesses two key structural features, namely the nucleophilic sulfur and the γ-glutamyl isopeptide bond. The former allows GSH to serve as a critical antioxidant and anti-electrophile. The latter allows GSH to translocate throughout the systemic circulation without being degraded. The kidneys exhibit several unique processes for handling GSH. This includes the extraction of 80% of plasma GSH, in part by glomerular filtration but mostly by transport across the basolateral plasma membrane. Studies on the protective effect of exogenous GSH are summarized, showing the different inherent susceptibility of proximal tubular and distal tubular cells and the impact on pathological or disease states, including hypoxia, diabetic nephropathy, and compensatory renal growth associated with uninephrectomy. Studies on mitochondrial GSH transport show the coordination between the citric acid cycle and oxidative phosphorylation in generating driving forces for both plasma membrane and mitochondrial carriers. The strong protective effects of increasing expression and activity of these carriers against oxidants and mitochondrial toxicants are summarized. Although GSH plays a cytoprotective role in most situations, two distinct exceptions to this are presented. In contrast to expectations, overexpression of the mitochondrial 2-oxoglutarate carrier markedly increased cell death from exposure to the nephrotoxic chemotherapeutic drug cisplatin (CDDP). Another key example of GSH serving a bioactivation role in the kidneys, rather than a detoxification role, is the metabolism of halogenated alkenes such as trichloroethylene (TCE). Although considerable research has gone into this topic, unanswered questions and emerging topics remain and are discussed.