Elham Ahmadian
Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Abstract
Mitochondria are potential targets of drug-related nephrotoxicity, and disruption of mitochondrial function in every single process could interfere with the proper function of the kidney. In spite of the widespread reports of drug-induced nephrotoxicity, the underlying mechanisms of these toxicities remain vague. Chemical reabsorption of kidney tubules as an active process depends on ATP consumption. Different kinds of xenobiotic and/or drugs can cause nephrotoxicity and mitochondria have an essential role in nephrotoxicity induced by drugs and/or xenobiotic. The critical role of mitochondrial dysfunction, oxidative hazard and altered ATP levels in the progression of drug-related nephrotoxicity have been reviewed in this study.
Keywords: Nephrotoxicity, Kidney, Mitochondrial damages
1. Introduction
Literature search has fetched several nephrotoxicity conditions upon exposure to xenobiotics/drugs, which restricts their clinical use [1, 2]. The clinical manifestations of kidney damages are reported as disruptions of serum electrolytes and altered amounts of chemicals such as proteins, glucose, and amino-acids in urinary specimens [3]. In spite of the widespread reports of drug-induced nephrotoxicity, the underlying mechanisms of these toxicities remain vague. Chemical reabsorption of kidney tubules as an active process depends on ATP consumption [4]. Abundant mitochondria are found in the proximal tubules of the kidney, which provide high energy supplies [5]. The Na+ /K+ ATPase pump, which acts based on the electrochemical sodium gradient, is applied for the chemical reabsorption process [6]. It should be mentioned that the action of this pump is dependent on ATP. Different chemicals such as vitamins, amino acids, and glucose are imported into the bloodstream via the action of Na+ /K+ ATPase pump in the kidneys [7] Therefore, mitochondria are potential targets of drug-related nephrotoxicity [8], and disruption of mitochondrial function in every single process could interfere with the proper function of the kidney. The current review focuses on the role of mitochondria in nephrotoxicity induced by drugs and/or xenobiotic.
2. Chemical reabsorption process and mitochondria
Many cells in the body possess Na+/K+ ATPase enzyme, which plays a pivotal role in several endogenous processes including impulse transmissions of neurons and chemical absorption from the gut [9, 10]. The pump acts based on the gradient of N+, while K+ is sent into the cells. This provides the driving force for reabsorption of phosphate, proteins, glucose into the systemic blood [11]. Keeping in mind the energy-dependent action of the pump, any abnormal function of the ATP synthesis process within the cell would interfere with the activity of Na+/K+ ATPase. Mitochondria are responsible for the production of ATP in proximal tubules cells [4]. Mitochondrial oxidative phosphorylation generates the majority of the energy required in proximal tubule cells [5]. Thus, proximal tubule cells are potential targets of drug-related mitochondrial damages. Energy metabolism and ATP synthesis could be disrupted if the function of mitochondria is altered which in turn might lead to serum electrolyte disturbances. Thus, mitochondrial malfunctions and consequent events play a critical role in drug-induced renal injuries.
3. Drug-induced nephrotoxicity and mitochondria
Different kinds of xenobiotics and/or drugs can cause nephrotoxicity. The continuous exposure of human beings to heavy metals is inevitable. They could be absorbed into the body through different routes and induce several unwanted effects [12]. The reproductive system, liver, and kidneys are among the most affected organs. It has been shown that mitochondria play a major role in toxic effects caused by heavy metals [13]. In the kidneys, heavy metals can accumulate in proximal tubule cells and results in nephrotoxicity [14]. Some metals such as arsenic, mercury and lead especially accumulate in the matrix of mitochondria [15]. Oxidative hazard and mitochondrial dysfunction have been mentioned as underlying mechanisms of heavy metal-induced renal damages. Mechanistically, oxidative stress and mitochondrial injury seem to play a pivotal role in this context.
Immunosuppressant and antimetabolite drugs affect the production and activity of cellular nucleic acid and proteins. Nephrotoxicity has been reported as a common adverse effect linked with these agents. Methotrexate is an immune-modulating drug utilized in cancer treatment [16]. Deleterious effects of methotrexate on kidney have been reported in several in vitro and in vivo studies [17]. In addition, in a high dose of methotrexate treatment regimens, nephrotoxicity is a major problem. Also, methotrexate has resulted in serum electrolyte disturbances in clinical applications [18]. Renal injury has also been indicated in the use of pemetrexed, which is an analog of methotrexate [19]. Deficiencies in the antioxidant capacity of kidney and oxidative stress have been mentioned to have a role in this toxicity [20]. Oxidative stress consequences such as lipid peroxidation and depletion of cellular glutathione pools have been observed in methotrexate nephrotoxicity [21]. Indeed, different experiments have highlighted the role of mitochondria in this context [22]. Methotrexate can prohibit the function of the mitochondrial respiratory chain; inhibit the oxidative phosphorylation process and decrease oxygen uptake and ATP level [23]. Moreover, the evidence of methotrexate-related renal injury has been in connection with mitochondrial dysfunction [24].
Nephrotoxicity has been associated with the use of other certain chemotherapy agents. Disruption of mitochondrial function and mitochondrial-related apoptosis are suggested as key mediators of anti-cancer agents-mediated kidney damage [25]. This mitochondrial malfunction can eventually result in deprivation of ATP reservoirs, the decline of the function of Na+/K+ ATPase pump and disruption of the reabsorption process in renal tubules. Thus, mitochondria could be proposed as a potential target in this field. Since mitochondria are well-known sources of endogenous reactive oxygen species it is not surprising that mitochondrial damage and oxidative stress act as consistent events in drug-related toxicities[26].
Antiretrovirals are other important groups of the drug, which cause renal failure in spite of their pharmacological effects. Monitoring serum chemical levels and also glomerular filtration rate are seemed to be important in their application [27, 28]. Mitochondria have been considered to play in a key role in patients receiving this group of drugs. Depletion of mitochondrial DNA in the kidney has been observed in HIV patients receiving didanosine [29].
4. Conclusion
The essential role of mitochondrial dysfunction, oxidative hazard and altered ATP levels in the progression of drug-related nephrotoxicity have been reviewed in this study. Mitochondria are shown to be key elements in this context. According to the results, it is important to have a strict monitoring system in the renal activity of patients receiving nephrotoxic drugs. In addition, antioxidants or mitochondrial protecting agents might be useful in plummeting xenobiotic-related kidney damages, tubular reabsorption process, and other consequent events.
Acknowledgments
The authors state that there is no financial support for this study.
Conflict of interest
The authors have no conflict of interest in this paper.
References
Kintzel, P.E., Anticancer drug—induced kidney disorders. Drug safety, 2001: 24(1):19-38.
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Maleki Dizaj, S., Mokhtarpour, M., Shekaari, H., & Sharifi, S. (2019). Hydroxyapatite-gelatin nanocomposite films; production and evaluation of the physicochemical properties. Journal of Advanced Chemical and Pharmaceutical Materials (JACPM), 2(2), 111-115. Retrieved from http://advchempharm.ir/journal/index.php/JACPM/article/view/70
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