Hypoxia-inducible factor-1α activation improves renal oxygenation and mitochondrial function in early chronic kidney disease

Abstract

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.

Salidroside Attenuates Adriamycin-Induced Focal Segmental Glomerulosclerosis by Inhibiting the Hypoxia-Inducible Factor-1α Expression Through Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway

“…According to a research conducted by Tan et al [26], SAL may represent a novel therapeutic agent for the treatment and prevention of hypoxia and oxidative stress-related diseases via targeting HIF-1α, indicating the possible target of SAL in FSGS. HIF-1α is activated under hypoxia and promotes expression of genes involved in cell fate, angiogenesis, and glucose metabolism [11,12]. Zhang et al [27] have reported that blocking HIF-1α could inhibit the activation of both inflammatory response and oxidative stress.…”

“…Hypoxia-inducible factor-1α (HIF-1α) is activated under hypoxia and promotes expression of genes involved in cell fate, angiogenesis, and glucose metabolism [11,12]. HIF-1α plays a crucial role in pathogenesis of chronic kidney disease (CKD).…”

Bioactive food and exercise in chronic kidney disease: Targeting the mitochondria

“…Another hypothesis is that mitochondria dysfunction in CKD relates to haemodynamic adaptations, due to an oxygen supply‐demand mismatch with resulting hypoxia and activation of hypoxia‐inducible factor 1 (HIF‐1). This lowers mitochondrial oxygen consumption and superoxide production and increase mitochondrial volume density . Moreover, the uraemic toxin indoxyl sulphate generated from gut microbiota decreases the expression of PGC‐1α and increases autophagy in skeletal muscle .…”

“…This lowers mitochondrial oxygen consumption and superoxide production and increase mitochondrial volume density. 45 Moreover, the uraemic toxin indoxyl sulphate generated from gut microbiota decreases the expression of PGC-1α and increases autophagy in skeletal muscle. 5,38,40,43,[46][47][48] Lastly, since deficiency of essential minerals can accelerate mitochondrial decay, 49 iron deficiency is a common and clinically important concern in CKD.…”

Epigallocatechin-3-Gallate Attenuates Adriamycin-Induced Focal Segmental Glomerulosclerosis via Suppression of Oxidant Stress and Apoptosis by Targeting Hypoxia-Inducible Factor-1α/ Angiopoietin-Like 4 Pathway

“…For example, Li et al [9] demonstrated that EGCG could inhibit IGF-I-stimulated lung cancer angiogenesis through the down-regulation of HIF-1α and VEGF expression; Luo et al [10] verified that EGCG decreases the expression of HIF-1α and VEGF and cell growth in MCF-7 breast cancer cells. HIF-1α is activated under hypoxia and promotes expression of genes involved in cell fate, angiogenesis and glucose metabolism [11,12]. Some researches indicated that over-activation of HIF-1α promotes fibrosis and contributes to the development of CKD [13].…”