Hypoxia Responses in Physiology and Pathogenesis
Changes in tissue oxygen levels occur under pathological conditions and physiologically during development. The laboratory of Volker Haase studies hypoxia response pathways and their therapeutic applications.
Volker Haase Lab
The laboratory of Professor Volker Haase studies hypoxia response pathways and their therapeutic applications in erythropoiesis and iron metabolism, chronic kidney injury and ischemic pre-conditioning, inflammation, kidney development and tumorigenesis. A major focus of the lab is on the interplay between hypoxia signaling, metabolism and cellular differentiation and its regulation by the prolyl hydroxylase domain (PHD) / hypoxia-inducible factor (HIF) / von Hippel-Lindau tumor suppressor (VHL) signaling axis. Haase group members take advantage of powerful cutting-edge mouse genetics, biochemical, metabolomic and single cell approaches to study oxygen and mitochondrial metabolism in kidney, urologic and other diseases. Click on links for information about career opportunities in the Haase lab and recent publications.
Lab news and updates
Erythropoietic effects of vadadustat in phase 3 trials
Congrats to Mark Koury and colleagues. This study investigates the effects of vadadustat on erythropoiesis and iron metabolism
Jun 2022
Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease
Patients with chronic kidney disease develop anemia largely because of inappropriately low erythropoietin production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non−dialysis-dependent patients with chronic kidney disease and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was non-inferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum erythropoietin, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. > …
Kidney EPO production in CKD is limited by myofibroblast transdifferentiation
This study from our lab demonstrates that HIF-PHIs do not stimulate EPO production in myofibroblasts
May 2022
EPO synthesis induced by HIF-PHD inhibition is dependent on myofibroblast transdifferentiation and colocalizes with non-injured nephron segments in murine kidney fibrosis
Erythropoietin (EPO) is regulated by hypoxia-inducible factor (HIF)-2. In the kidney, it is produced by cortico-medullary perivascular interstitial cells, which transdifferentiate into collagen-producing myofibroblasts in response to injury. Inhibitors of prolyl hydroxylase domain (PHD) dioxygenases (HIF-PHIs) activate HIF-2 and stimulate kidney and liver EPO synthesis in patients with anemia of chronic kidney disease (CKD). We examined whether HIF-PHIs can reactivate EPO synthesis in interstitial cells that have undergone myofibroblast transdifferentiation in established kidney fibrosis. > …
see commentary: The prolyl hydroxylase inhibitor molidustat fails to restore erythropoietin production in the fibrotic kidney [Acta Physiologica 2022].
HIF activation prevents bladder injury
This study from our lab demonstrates that HIF-activating compounds protect from cystitis
May 2022
Inhibition of hypoxia-inducible factor-prolyl hydroxylation protects from cyclophosphamide-induced bladder injury and urinary dysfunction
Disruption of the blood-urine barrier can result in acute or chronic inflammatory bladder injury. Activation of the oxygen-regulated hypoxia-inducible factor (HIF) pathway has been shown to protect mucosal membranes by increasing the expression of cytoprotective genes and by suppressing inflammation. The activity of HIF is controlled by prolyl hydroxylase domain (PHD) dioxygenases, which have been exploited as therapeutic targets for the treatment of anemia of chronic kidney disease. Here we established a mouse model of acute cyclophosphamide (CYP)-induced blood-urine barrier disruption associated with inflammation and severe urinary dysfunction to investigate the HIF-PHD axis in inflammatory bladder injury. We found that systemic administration of dimethyloxalylglycine (DMOG) or molidustat, two small molecule inhibitors of HIF-prolyl hydroxylases (HIF-PHIs), profoundly mitigated CYP-induced bladder injury and inflammation as assessed by morphologic analysis of transmural edema and urothelial integrity and by measuring tissue cytokine expression. > …
HypoxEU Live in Dublin, Ireland
International meeting on hypoxia and oxygenation
Meet Haase lab members at this meeting.
Sept 11-13, 2022
For information on the meeting please click here.
Anemia of CKD
Commentary: Iron absorption
April 2022
The ins and outs of ferric citrate
Ferric citrate is used clinically for the treatment of hyperphosphatemia in patients with chronic kidney disease and is approved as an oral iron replacement product for patients with iron-deficiency anemia. In this issue of Kidney International, Hanudel and colleagues take advantage of genetic models with and without chronic kidney injury to demonstrate that the enteric absorption of iron delivered by ferric citrate is dependent on ferroportin expression and does not involve paracellular iron transport. > …
The Haase lab will present at the Keystone meeting on hypoxia in Killarney, Ireland
Hypoxia: From Basic Mechanisms to Emerging Therapies
May 28-31, 2023
Scientific Organizers: Sonia Rocha, Edurne Berra and M. Celeste Simon. For information on the meeting please click here.
(click on image for program information)
Mitochondrial electron transport in renal development
This study from our lab identifies a differential role for mitochondrial electron transport in renal progenitors
March 2022
Disruption of mitochondrial complex III in cap mesenchyme but not in ureteric progenitors results in defective nephrogenesis associated with amino acid deficiency.
Oxidative metabolism in mitochondria regulates cellular differentiation and gene expression through intermediary metabolites and reactive oxygen species. Its role in kidney development and pathogenesis is not completely understood. Here we inactivated ubiquinone-binding protein QPC, a subunit of mitochondrial complex III, in two types of kidney progenitor cells to investigate the role of mitochondrial electron transport in kidney homeostasis. Inactivation of QPC in sine oculis-related homeobox 2 (SIX2)-expressing cap mesenchyme progenitors, which give rise to podocytes and all nephron segments except collecting ducts, resulted in perinatal death from severe kidney dysplasia. > …
New insights into the effects of pharmacological HIF activation on renal hemodynamics
This study from our lab identifies a major role for HIF-dependent NO generation in GFR regulation
April 2021
Pharmacological HIF-PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation
HIF-activating compounds are currently in late-stage clinical development for the treatment of anemia associated with chronic kidney disease. Although the effects of hypoxia on renal hemodynamics and function have been studied in animal models and in humans living at high altitude, the effects of pharmacologic HIF activation on renal hemodynamics, O2 metabolism and metabolic efficiency are not well understood. This cross-sectional study in healthy rats provides new mechanistic insights into dose-dependent effects of short-term pharmacologic HIF activation on renal hemodynamics, glomerular filtration and O2 metabolism. > …
see commentary: Get used to the -dustats: Roxadustat and molidustat, members of the hypoxia-inducible factor (HIF) Prolyl hydroxylase (PHD) inhibitor drug class promote kidney function, perfusion and oxygenation in rats through nitric oxide [Acta Physiologica 2021].
KDIGO Conference Report on Optimal Anemia Management
April 2021
Controversies in Optimal Anemia Management: Conclusions from a Kidney Disease Improving Global Outcomes (KDIGO) Conference
In 2019, KDIGO decided to convene two Controversies Conferences to review the latest evidence, explore new and ongoing controversies, assess change implications for the current KDIGO anemia guideline, and propose a research agenda. The first conference, described here, focused mainly on iron-related issues, including the contribution of disordered iron homeostasis to the anemia of CKD, diagnostic challenges, available and emerging iron therapies, treatment targets, and patient outcomes. > …
Anemia of CKD
Update on the clinical science of HIF-prolyl hydroxylase inhibitors in anemia of CKD
March 2021
Hypoxia-inducible factor-prolyl hydroyxlase inhibitors in the treatment of anemia of chronic kidney disease
This review summarizes clinical data from current HIF-PHI trials in patients with anemia of CKD, discusses mechanisms of action and pharmacologic properties of HIF-PHIs, and deliberates over safety concerns and potential impact on anemia management in patients with CKD. > …