Metabolic mechanisms of acute proximal tubular injury

Abstract

Damage to the proximal tubule (PT) is the most frequent cause of acute kidney injury (AKI) in humans. Diagnostic and treatment options for AKI are currently limited, and a deeper understanding of pathogenic mechanisms at a cellular level is required to rectify this situation. Metabolism in the PT is complex and closely coupled to solute transport function. Recent studies have shown that major changes in PT metabolism occur during AKI and have highlighted some potential targets for intervention. However, translating these insights into effective new therapies still represents a substantial challenge. In this article, in addition to providing a brief overview of the current state of the field, we will highlight three emerging areas that we feel are worthy of greater attention. First, we will discuss the role of axial heterogeneity in cellular function along the PT in determining baseline susceptibility to different metabolic hits. Second, we will emphasize that elucidating insult specific pathogenic mechanisms will likely be critical in devising more personalized treatments for AKI. Finally, we will argue that uncovering links between tubular metabolism and whole-body homeostasis will identify new strategies to try to reduce the considerable morbidity and mortality associated with AKI. These concepts will be illustrated by examples of recent studies emanating from the authors’ laboratories and performed under the auspices of the Swiss National Competence Center for Kidney Research (NCCR Kidney.ch).

Transmission of high arterial pressure into renal microvessels during venous‐clamping augments ischaemia/reperfusion‐induced acute kidney injury in anaesthetized rats

“…In the post-ischaemic kidney, tubular injuries can be either lethal as apoptosis and necrosis or sublethal as disintegrations in cytoskeleton and intercellular junctional proteins, detachment of viable cells, shedding of brush borders and formation of intratubular casts. 1,[21][22][23] The most drastic epithelial cell damages in both VIR and VIR-rRPP groups occurred in the PT and TAL, because of their high active transport, 24,25 and especially in the OM-os where is primarily supplied by venous blood of ascending vasa and with a hypoxic state even in the normal condition. 18,19,23 It has been shown that bilateral renal arterial clamping in the male spontaneously hypertensive rats (SHR) compared with the female SHR and normotensive male rats results in greater VC, especially in the OM, which is associated with the development of severer AKI and more delay in recovery of the post-ischaemic kidney.…”

Urinary Concentration of Renal Biomarkers in Healthy Term Neonates: Gender Differences in GST-pi Excretion

“…The proximal renal tubule is a major site for tubular damage and proximal tubule injury is the most frequent cause of AKI. Therefore, it is important to identify the site of injury [ 55 ].…”

CD44 expression in renal tubular epithelial cells in the kidneys of rats with cyclosporine-induced chronic kidney disease

“…Drug-induced kidney injury (DIKI) is a major concern in the clinical use of nephrotoxic drugs as well as in the drug development process 1,2 . Renal tubular epithelial cells (TECs) are particularly sensitive to druginduced toxicity because of their pivotal role in the reabsorption and metabolism of xenobiotics 3,4 . Acute tubular necrosis is the most common cause of acute kidney injury (AKI) 5 .…”