Multifaceted roles of tubulointerstitial hypoxia in chronic kidney disease

Chronic hypoxia in the tubulointerstitial compartment of the kidney is a commonmediator of injury in many forms of chronic kidney disease (CKD). Both experimentaland human pathological studies support the view that the loss of the peritubular capillarynetwork is associated with tubulointerstitial injury and a decrease in residual renalfunction. The therapeutic role of angiogenic factors and vasoactive substances such asvascular-endothelial growth factor has been extensively studied in animal models ofCKD. On the other hand, an incommensurate increase in oxygen consumption; i.e, anincrease in oxygen consumption (QO₂) over sodium reabsorption (TNa) (QO₂/TNa), mayalso contribute to a fall in tissue oxygen tension, particularly under the high angiotensinII and low nitric oxide conditions that are frequently encountered in CKD.Hypoxia-inducible factor (HIF) is a master transcription factor mediating cellularadaptive responses to hypoxia. In the kidney, HIF-1α is expressed in the tubular epithelialcells, glomerular epithelium, and papillary interstitial cells, whereas HIF-2α is expressedin the interstitial and vascular compartments following ischemic insult. Studies inknockout mice and rodents with chemical and pharmacological activation of HIF suggestthe protective role of HIF in acute kidney injury, but the role of HIF in CKD is elusiveand appears to be multifaceted. In some types of progressive glomerular disease, HIFameliorates tubulointerstitial injury by counteracting tubular cell apoptosis, preserving peritubular capillary networks, and decreasing proteinuria. In several other nonglomerulardiseases, it may accelerate fibrotic changes. Excessive HIF activity may also beinvolved in loss of cilia and epithelial cyst formation. Moreover, evidence suggests that acertain HIF target gene product may serve as a glomerular permeability factor that leadsto massive proteinuria.These observations underscore the multifaceted, context-dependent role of HIF, andemphasize the critical involvement of hypoxia in the pathogenesis of progressive renaldisease.