Diverse Roles of Mitochondria in Renal Injury from Environmental Toxicants and Therapeutic Drugs

Abstract

Mitochondria are well-known to function as the primary sites of ATP synthesis in most mammalian cells, including the renal proximal tubule. Other functions have also been associated with different mitochondrial activities, including the regulation of redox status and the initiation of mitophagy and apoptosis. Mechanisms for the membrane transport of glutathione (GSH) and various GSH-derived metabolites across the mitochondrial inner membrane of renal proximal tubular cells are critical determinants of these functions and may serve as pharmacological targets for potential therapeutic approaches. Specific interactions of reactive intermediates, derived from drug metabolism, with molecular components in mitochondria have been identified as early steps in diverse forms of chemically-induced nephrotoxicity. Applying this key observation, we developed a novel hypothesis regarding the identification of early, sensitive, and specific biomarkers of exposure to nephrotoxicants. The underlying concept is that upon exposure to a diverse array of environmental contaminants, as well as therapeutic drugs whose efficacy is limited by nephrotoxicity, renal mitochondria will release both high- and low-molecular-weight components into the urine or the extracellular medium in an in vitro model. The detection of these components may then serve as indicators of exposure before irreversible renal injury has occurred.

Cadmium-Induced Kidney Injury: Oxidative Damage as a Unifying Mechanism

“…The kidney is also vulnerable to injuries caused by numerous challenges such as ischemia [ 8 , 9 , 10 , 11 , 12 ], drug toxicity [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ], environmental heavy metal exposure [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ], hypertension [ 28 , 29 , 30 ], immune injury [ 31 , 32 ], and diabetes [ 33 , 34 , 35 , 36 ]. In terms of environmental risk factors, human kidney disease caused by environmental pollutants and occupational-linked toxins is a major public health issue [ 37 ].…”

Precision nephrotoxicity testing using 3D in vitro models

“…Some commonly used drugs for nephrotoxicity testing include aminoglycosides, cisplatin, NSAIDs, and antimicrobials (Table 4). Most of these drugs cause renal toxicity by reducing ATP generation, DNA, mitochondria function, and inducing oxidative stress, and cell apoptosis [75,76] Based on tissue injury type and clinical presentation, antimicrobial-induced nephropathy may result in acute tubular necrosis, acute interstitial nephritis and crystal (obstructive) nephropathy.…”