Oxygen Sensing in Kidney Injury 2018-03-31T04:22:35+00:00

Oxygen Sensing in Kidney Injury

Hypoxia has been identified as a final and common pathway in the pathogenesis of chronic kidney disease (CKD) irrespective of etiology, as demonstrated by the Haase group and other laboratories. The importance of the HIF oxygen sensing pathway for the pathogenesis of CKD, fibrotic diseases and inflammation became first evident when the Haase laboratory observed that the expression of HIF-1α was increased in renal biopsy material from patients with diabetic nephropathy. Using mouse genetics Professor Haase’s group then identified HIF-1 as the first molecular link between hypoxia and CKD progression (Higgins et al., JCI, 2007).

Central hypothesis of Professor Haase’s research program is that hypoxia, the HIF/PHD pathway and other oxygen- and 2OG-dependent dioxygenases play critical roles in the pathogenesis of renal injury and CKD progression through the regulation of metabolic pathways, mitochondrial metabolism and inflammation. Shifts in cellular metabolism provide specific signals that modulate cellular differentiation and function, cell-cell interactions and inflammation, and thus can lead to maladaptive tissue repair impacting the development and progression of fibrotic diseases, such as CKD.

Specifically, the Haase laboratory was able to show that changes in epithelial mitochondrial metabolism modulate the function of pericytes and renal microvasculature through changes in renal tissue pO2. Professor Haase’s group has furthermore shown that the activation of hypoxia responses in renal endothelium modulates inflammatory responses in the context of acute and chronic renal injury.

The long-term goals of Haase’s research program are to characterize the molecular links between oxygen sensing, renal metabolism, inflammation and chronic kidney injury. Data generated from this research program will provide general insights into the role of oxygen metabolism in tissue injury and repair and will be of relevance to multiple organ systems.

Relevant Publications from the Haase Lab

  • Cho SH, Raybuck AL, Stengel K, Wei M, Beck TC, Volanakis E, Thomas JW, Hiebert S, Haase VH, Boothby MR. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature. 2016 Aug 8;537(7619):234-238. PubMed PMID: 27501247.
  • Kobayashi H, Gilbert V, Liu Q, Kapitsinou PP, Unger TL, Rha J, Rivella S, Schlöndorff D, Haase VH. Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury. J Immunol. 2012 May 15;188(10):5106-15. PubMed PMID: 22490864; PubMed Central PMCID: PMC3345098.
  • Peng M, Falk MJ, Haase VH, King R, Polyak E, Selak M, Yudkoff M, Hancock WW, Meade R, Saiki R, Lunceford AL, Clarke CF, Gasser DL. Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease. PLoS Genet. 2008 Apr 25;4(4):e1000061. PubMed PMID: 18437205; PubMed Central PMCID: PMC2291193.
  • Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, Haase VH. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 2007 Dec;117(12):3810-20. PubMed PMID: 18037992; PubMed Central PMCID: PMC2082142.