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The Proximal Tubule as the Pathogenic and Therapeutic Target in Acute Kidney Injury

Ho, K.M. and Morgan, D.J.R. (2022) The Proximal Tubule as the Pathogenic and Therapeutic Target in Acute Kidney Injury. Nephron . pp. 1-9.

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Background: In 2004, the term acute kidney injury (AKI) was introduced with the intention of broadening our understanding of rapid declines in renal function and to replace the historical terms of acute renal failure and acute tubular necrosis (ATN). Despite this evolution in terminology, the mechanisms of AKI have stayed largely elusive with the pathophysiological concepts of ATN remaining the mainstay in our understanding of AKI. Summary: The proximal tubule (PT), having the highest mitochondrial content in the kidney and relying heavily on oxidative phosphorylation to generate ATP, is vulnerable to ischaemic insults and mitochondrial dysfunction. Histologically, pathological changes in the PT are more consistent than changes to the glomeruli or the loop of Henle in AKI. Physiologically, activation of tubuloglomerular feedback due to PT dysfunction leads to an increase in preglomerular afferent arteriole resistance and a reduction in glomerular filtration. Pharmacologically, frusemide – a drug commonly used in the setting of oliguric AKI – is actively secreted by the PT and its diuretic effect is compromised by its failure to be secreted into the urine and thus be delivered to its site of action at the loop of Henle in AKI. Increases in the urinary, but not plasma biomarkers, of PT injury within 1 h of shock suggest that the PT as the initiation pathogenic target of AKI. Key Message: Therapeutic agents targeting specifically the PT epithelial cells, in particular its mitochondria – including amino acid ergothioneine and superoxide scavenger MitoTEMPO – show great promises in ameliorating AKI.

Item Type: Journal Article
Murdoch Affiliation(s): School of Veterinary and Life Sciences
Publisher: Karger AS
Copyright: © 2022 S. Karger AG, Basel
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