Hypoxia Responses in Physiology and Pathogenesis

Changes in tissue oxygen levels occur under physiological and pathological conditions. The laboratory of Volker Haase studies hypoxia response pathways and their therapeutic applications.

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Volker Haase Lab

Oxygen logo Volker H Haase Laboratory

The laboratory of Professor Volker Haase studies hypoxia response pathways 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 publications.

Mitochondria renal epithelium

Mitochondria in renal epithelium

Epo RNA-FISH Volker Haase Lab

Erythropoietin-producing cells in the kidney
(red fluorescent signal)

Overwiew of oxygen metabolism in renal tissue

Mechanisms of Renal Hypoxia

Epithelial progenitor cells in the developing kidney

Haase Lab in 2017

Lab News and Updates

commentary

Anemia of CKD

HIF-PHIs in kidney transplant patients

April 2024

Hypoxia-Inducible Factor Stabilizers: An Evolving Role in Post-Transplant Anemia

Anemia after kidney transplantation develops for a variety of reasons so that treatment should be targeted to the underlying etiology. In this setting erythropoiesis stimulating agents (ESAs) can be employed as in other patients with nondialysis CKD anemia. But the use of these agents has probably been somewhat limited by the need for parenteral administration and perhaps by safety concerns. In contrast to ESAs, HIF-PHIs are administered orally and thereby have the potential to simplify treatment. These drugs work by stabilizing hypoxia inducible factor, leading to erythropoietin production and improved iron availability. They have been extensively studied in nondialysis as well as dialysis CKD populations. Kong and colleagues report on a study of the hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), roxadustat, for the treatment of post-transplant anemia. > …
commentary

Anemia of CKD

Iron regulation

June 2023

Deregulating iron-erythropoiesis regulation: transferrin receptor 2 as potential target for treating anemia in CKD

Both insufficient kidney production of erythropoietin and inflammation-mediated reduction of transferrin-bound iron are major factors in anemia of chronic kidney disease. Improved therapies for anemia in chronic kidney disease may involve modifying regulators of erythropoiesis and iron availability. Olivari et al. show in a model of chronic kidney disease that transferrin receptor 2 in hepatocytes, where it is required for hepcidin production, and in erythroid cells, where it downregulates erythropoietin receptor activity, is a potential therapeutic target. > …

conference report

KDIGO Conference Report on Optimal Anemia Management II

May 2023

Novel Anemia Therapies in CKD: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Beginning in 2019, KDIGO planned two Controversies Conferences to review new evidence and its potential impact on the management of anemia associated with chronic kidney disease. The second of these conferences was held virtually in December 2021 and focused on a new class of agents, the hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs). This report provides a review of the consensus points and controversies from this second conference and highlights areas that warrant prioritization for future research. > …

original research

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

HIF in iron metabolismErythropoietic 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. > …

original research

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

Kobayashi et al., Acta Physiologica 2002EPO 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].

original research

HIF activation prevents bladder injury

This study from our lab demonstrates that HIF-activating compounds protect from cystitis

May 2022

Clayton et al., AJP Renal, 2022Inhibition 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. > …