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

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. TFAM deficiency resulted in significantly decreased mitochondrial gene expression, mitochondrial depletion, inhibition of nephron maturation and the development of severe postnatal cystic disease, which resulted in premature death. > ...

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

New insights into the role of glycogen as an energy resource in acute kidney injury

April 2020

A perspective in Kidney International on how renal glycogen metabolism may contribute to cytoprotection afforded by pre-ischemic HIF–prolyl hydroxylase inhibition.

for link to editorial click here

Kyoji Yamaguchi joins the Haase group

November 2019

The Haase lab welcomes Dr. Kyoji Yamaguchi. Dr. Yamaguchi joined the Vanderbilt faculty coming from Japan where he led a drug discovery program in a prominent pharmaceutical company and developed HIF-prolyl hydroxylase inhibitors for the treatment of anemia and chronic kidney disease.

for information on current Haase group members and alumni click here

Review published on current clinical experience with HIF-activators in renal anemia therapy

August 2019

Hypoxia-inducible factor activators in renal anemia: Current clinical experience

Prolyl hydroxylase domain (PHD) oxygen sensors are dioxygenases that regulate the activity of hypoxia-inducible factor (HIF). Small molecule inhibitors of PHD dioxygenases stimulate the production of endogenous EPO and improve iron metabolism resulting in effective anemia management in patients with chronic kidney disease. In this review Volker Haase and Neil Sanghani survey current clinical experience with HIF-PHIs, discuss potential therapeutic advantages and deliberate over safety concerns regarding long-term administration in patients with renal anemia. > …

link to erythropoiesis, iron metabolism and renal anemia

link to media files on renal anemia