Effects of HIF prolyl hydroxylase inhibition in models of chronic kidney disease

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Chronic kidney diseases are regularly associated with chronic hypoxia due to concomitant pathophysiological processes like interstitial fibrosis and capillary rarefaction. Under hypoxia, a central regulatory factor is the transcription factor Hypoxia Inducible Factor (HIF) which controls numerous cellular processes like angiogenesis, erythropoiesis or glycolysis, which altogether allows tissues to adapt to low oxygen concentrations. In order to induce erythropoietin, newly developed HIF stabilizers are already under clinical evaluation. On the other hand HIF has also been associated with profibrotic, potentially deleterious effects. To this end, it is not clear which effects HIF stabilisation by Prolyl hydroxylase inhibition will have in progressive kidney disease and if HIF stabilisation may have protective effects. HIF Prolyl hydroxylases hydroxylate the HIF protein which targets it for cellular proteasomal degradation. In complementary mouse models of chronic kidney diseases the functional importance of HIF stabilisation in the kidney should be analyzed. Firstly, the prolyl hydroxylase-2 or the vhl gene will be genetically inactivated and secondly newly synthesized ketoglutarate analogues will be applied, which selectively can inhibit the PHDs in renal epithelial cells.