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The Role of Mitochondria in Drug-Induced Kidney Injury


Gai, Zhibo; Gui, Ting; Kullak-Ublick, Gerd A; Li, Yunlun; Visentin, Michele (2020). The Role of Mitochondria in Drug-Induced Kidney Injury. Frontiers in Physiology, 11:1079.

Abstract

The kidneys utilize roughly 10% of the body’s oxygen supply to produce the energy required for accomplishing their primary function: the regulation of body fluid composition through secreting, filtering, and reabsorbing metabolites and nutrients. To ensure an adequate ATP supply, the kidneys are particularly enriched in mitochondria, having the second highest mitochondrial content and thus oxygen consumption of our body. The bulk of the ATP generated in the kidneys is consumed to move solutes toward (reabsorption) or from (secretion) the peritubular capillaries through the concerted action of an array of ATP-binding cassette (ABC) pumps and transporters. ABC pumps function upon direct ATP hydrolysis. Transporters are driven by the ion electrochemical gradients and the membrane potential generated by the asymmetric transport of ions across the plasma membrane mediated by the ATPase pumps. Some of these transporters, namely the polyspecific organic anion transporters (OATs), the organic anion transporting polypeptides (OATPs), and the organic cation transporters (OCTs) are highly expressed on the proximal tubular cell membranes and happen to also transport drugs whose levels in the proximal tubular cells can rapidly rise, thereby damaging the mitochondria and resulting in cell death and kidney injury. Drug-induced kidney injury (DIKI) is a growing public health concern and a major cause of drug attrition in drug development and post-marketing approval. As part of the article collection “Mitochondria in Renal Health and Disease,” here, we provide a critical overview of the main molecular mechanisms underlying the mitochondrial damage caused by drugs inducing nephrotoxicity.

Abstract

The kidneys utilize roughly 10% of the body’s oxygen supply to produce the energy required for accomplishing their primary function: the regulation of body fluid composition through secreting, filtering, and reabsorbing metabolites and nutrients. To ensure an adequate ATP supply, the kidneys are particularly enriched in mitochondria, having the second highest mitochondrial content and thus oxygen consumption of our body. The bulk of the ATP generated in the kidneys is consumed to move solutes toward (reabsorption) or from (secretion) the peritubular capillaries through the concerted action of an array of ATP-binding cassette (ABC) pumps and transporters. ABC pumps function upon direct ATP hydrolysis. Transporters are driven by the ion electrochemical gradients and the membrane potential generated by the asymmetric transport of ions across the plasma membrane mediated by the ATPase pumps. Some of these transporters, namely the polyspecific organic anion transporters (OATs), the organic anion transporting polypeptides (OATPs), and the organic cation transporters (OCTs) are highly expressed on the proximal tubular cell membranes and happen to also transport drugs whose levels in the proximal tubular cells can rapidly rise, thereby damaging the mitochondria and resulting in cell death and kidney injury. Drug-induced kidney injury (DIKI) is a growing public health concern and a major cause of drug attrition in drug development and post-marketing approval. As part of the article collection “Mitochondria in Renal Health and Disease,” here, we provide a critical overview of the main molecular mechanisms underlying the mitochondrial damage caused by drugs inducing nephrotoxicity.

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Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Physiology
Health Sciences > Physiology (medical)
Uncontrolled Keywords:Physiology (medical), Physiology
Language:English
Date:4 September 2020
Deposited On:12 Feb 2021 15:20
Last Modified:13 Feb 2021 21:00
Publisher:Frontiers Research Foundation
ISSN:1664-042X
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.3389/fphys.2020.01079
PubMed ID:33013462
Project Information:
  • : FunderSNSF
  • : Grant ID310030_175639
  • : Project TitleRole of drug transporters and nuclear receptors in drug-induced liver and kidney injury

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