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, 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.

Mitochondria in renal epithelium

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

Lab news and updates

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 use 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. > ...

Mitochondrial transcription factor TFAM in renal cystic disease

This study from our lab uncovered a critical role for TFAM in nephron maturation and renal cytogenesis using mouse genetics

November 2020

Renal epithelial TFAM deficiency results in progressive mitochondrial depletion associated with severe cystic disease

Abnormal mitochondrial function is a well-recognized feature of acute and chronic kidney diseases. To gain insight into the role of mitochondria in kidney homeostasis and pathogenesis, we targeted mitochondrial transcription factor A (TFAM), a protein required for mitochondrial DNA replication and transcription that plays a critical part in the maintenance of mitochondrial mass and function. To examine the consequences of disrupted mitochondrial function in kidney epithelial cells, we inactivated TFAM in sine oculis-related homeobox 2-expressing kidney progenitor cells. > ...

A role for hypoxic signaling in glomerular-tubulointerstitial cross-talk during renal injury

Congrats to Agnes, Hai-Chun and colleagues on the acceptance of their paper

October 2020

Stabilization of Hypoxia-Inducible Factor Ameliorates Glomerular Injury Sensitization after Tubulointerstitial Injury

Previously, we found that mild tubulointerstitial injury sensitizes glomeruli to subsequent injury. Here, we evaluated whether stabilization of hypoxia-inducible factor-α (HIF-α), a key regulator of tissue response to hypoxia, ameliorates tubulointerstitial injury and impact on subsequent glomerular injury. Nep25 mice, which express the human CD25 receptor on podocytes under control of the nephrin promotor and develop glomerulosclerosis when a specific toxin is administered were used. Tubulointerstitial injury, evident by week two, was induced by folic acid, and mice were treated with an HIF stabilizer, dimethyloxalylglycine or vehicle from week three to six. Uninephrectomy at week six assessed tubulointerstitial fibrosis. Glomerular injury was induced by podocyte toxin at week seven, and mice were sacrificed ten days later. > ...

Dissecting the role of HIF-prolyl 4-hydroxylase oxygen sensors in neurovascular homeostasis

Congratulations to Andres Urrutia on his new paper in Acta Physiologica

August 2020

Inactivation of HIF-prolyl 4-hydroxylases 1, 2 and 3 in NG2-expressing cells induces HIF2-mediated neurovascular expansion independent of erythropoietin (cover)

The study looks at the role of brain pericyte oxygen sensing and erythropoietin in neurovascular homeostasis.

for link to article click here

for link to commentary on this article click here

link to cover page