Hypoxia Inducible Factor Activation Prevents Renal Mitochondria Dysfunction and Improves Cortical Oxygenation in Type 1 Diabetic Mice

Hypoxia‐inducible factors (HIFs) are transcription factors that are activated during hypoxia in order to regulate a hypoxic gene response. During normoxia, prolyl hydroxylase domain‐containing protein 2 (PHD2) is one of three isoforms that acts on HIF as a first step towards its degradation and its knockdown consequently results in HIF activation. Previous studies have demonstrated that diabetes induces mitochondria dysfunction resulting in renal cortical hypoxia, yet studies indicate that hyperglycemia impairs HIF stabilization resulting in suboptimal activation and an inability to correct renal hypoxia. In this study, we hypothesize that increased HIF‐activation resulting from PHD2 knockdown, prevents mitochondria dysfunction and improves renal oxygenation in type 1 diabetic mice. Balb/c mice from four groups (Wild type normoglycemic (n=16), wild type diabetic (n=10), PHD2 +/− normoglycemic (n=16) and PHD2 +/− diabetic (n=11)) were placed in metabolic cages for 24 h urine collection followed by conscious determination glomerular filtration rate (GFR), using a single bolus injection of FITC‐inulin. Diabetes was induced by a low dose injection of strepzotocin (i.p.) for 5 consecutive days and diabetes duration was 5–6 weeks. Renal cortical oxygenation was measured with Clark electrodes and kidney mitochondria function, including mitochondria proton leak, was assessed by high resolution respirometry. Urinary excretion of albumin and thiobarbituric acid reactive species were measured and corrected for 24 h urine volume. Diabetes resulted in increased GFR in both groups compared to normoglycemic mice. Wild type diabetic mice presented with increased total mitochondrial leak respiration compared to normoglycemic mice, which was prevented in the PHD2 +/− mice. Interestingly, regulated leak, defined as mitochondrial proton leak regulated by uncoupling proteins and adenosine nucleotide translocase, was increased in diabetic PHD2 +/− only, while unregulated leak, defined as total leak minus regulated leak, was increased in wild type diabetic mice. Both diabetic groups displayed increased albuminuria and thiobarbituric acid reactive species compared to normoglycemic control mice. In conclusion, activation of HIF by reducing PHD2 expression prevents mitochondria dysfunction and renal cortical hypoxia in type 1 diabetic mice. This could imply a novel target for the PHD inhibitors currently in clinical trials. Support or Funding Information This study was supported financially by the Swedish Research Council, the Swedish Diabetes Foundation and the Family Ernfors Fund. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .