Hypoxia-inducible factor-1α activation improves renal oxygenation and mitochondrial function in early chronic kidney disease.
The pathophysiology of chronic kidney disease (CKD) is driven by alterations in surviving nephrons to sustain renal function with ongoing nephron loss. Oxygen supply-demand mismatch, due to hemodynamic adaptations, with resultant hypoxia, plays an important role in the pathophysiology in early CKD. We sought to investigate the underlying mechanisms of this mismatch. We utilized the subtotal nephrectomy (STN) model of CKD to investigate the alterations in renal oxygenation linked to sodium (Na) transport and mitochondrial function in the surviving nephrons. Oxygen delivery was significantly reduced in STN kidneys because of lower renal blood flow. Fractional oxygen extraction was significantly higher in STN. Tubular Na reabsorption was significantly lower per mole of oxygen consumed in STN. We hypothesized that decreased mitochondrial bioenergetic capacity may account for this and uncovered significant mitochondrial dysfunction in the early STN kidney: higher oxidative metabolism without an attendant increase in ATP levels, elevated superoxide levels, and alterations in mitochondrial morphology. We further investigated the effect of activation of hypoxia-inducible factor-1α (HIF-1α), a master regulator of cellular hypoxia response. We observed significant improvement in renal blood flow, glomerular filtration rate, and tubular Na reabsorption per mole of oxygen consumed with HIF-1α activation. Importantly, HIF-1α activation significantly lowered mitochondrial oxygen consumption and superoxide production and increased mitochondrial volume density. In conclusion, we report significant impairment of renal oxygenation and mitochondrial function at the early stages of CKD and demonstrate the beneficial role of HIF-1α activation on renal function and metabolism.
['Thomas|Joanna L|JL|', 'Pham|Hai|H|', 'Li|Ying|Y|', 'Hall|Elanore|E|', 'Perkins|Guy A|GA|', 'Ali|Sameh S|SS|', 'Patel|Hemal H|HH|', 'Singh|Prabhleen|P|']
D000255:Adenosine Triphosphate D000600:Amino Acids, Dicarboxylic D000818:Animals D015687:Cell Hypoxia D004195:Disease Models, Animal D004734:Energy Metabolism D005919:Glomerular Filtration Rate D051795:Hypoxia-Inducible Factor 1, alpha Subunit D007668:Kidney D008297:Male D008928:Mitochondria D010100:Oxygen D010101:Oxygen Consumption D017208:Rats, Wistar D012079:Renal Circulation D051436:Renal Insufficiency, Chronic D065608:Renal Reabsorption D015398:Signal Transduction D012964:Sodium D013481:Superoxides D013997:Time Factors
oxygenation CKD hypoxia metabolism mitochondria