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.

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-conditioninginflammation, 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.

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

Anemia of CKD

Commentary: 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. > …

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. >

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. > …

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].

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. > …

Anemia of CKD

Commentary: Iron absorption

April 2022

Commentary on intestinal iron absorption delivered as ferric citrate

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. > …

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. > …