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

The laboratory of Professor Volker Haase studies hypoxia response pathways in erythropoiesis and iron metabolism, acute and chronic kidney injury, 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

original research

Mitochondrial electron transport regulates aquaporin-2

Congratulations to Josh Carty, Ryoichi Bessho and team on the acceptance of their manuscript in JCI Insight. In this exciting study, we examine the role of oxidative phosphorylation in the regulation of body water homeostasis.

October 2024

Disruption of mitochondrial electron transport impairs urinary concentration via AMPK-dependent suppression of aquaporin-2

Urinary concentration is an energy-dependent process that minimizes body water loss by increasing aquaporin-2 (AQP2) expression in collecting duct (CD) principal cells. To investigate the role of mitochondrial (mt) ATP production in renal water clearance, we disrupted mt electron transport in CD cells by targeting ubiquinone (Q) binding protein QPC (UQCRQ), a subunit of mt complex III essential for oxidative phosphorylation. QPC-deficient mice produced less concentrated urine than controls, both at baseline and after type 2 vasopressin receptor stimulation with desmopressin. Impaired urinary concentration in QPC-deficient mice was associated with reduced total AQP2 protein levels in CD tubules, while AQP2 phosphorylation and membrane trafficking remained unaffected. In cultured inner medullary CD cells treated with mt complex III inhibitor antimycin A, the reduction in AQP2 abundance was associated with activation of  5’ adenosine monophosphate-activated protein kinase (AMPK) and was reversed by treatment with AMPK inhibitor SBI-0206965. > …
announcement

Bessho receives the Sharon Anderson Research Fellowship Award from the American Society of Nephrology

June 2024

Ryoichi Bessho, M.D., Ph.D.

Congratulations to Dr. Ryoichi Bessho, M.D., Ph.D, for receiving the Sharon Anderson Research Fellowship Award as part of the Ben J. Lipps Research Program of the American Society of Nephrology (ASN). Ryoichi trained as an Endocrinologist at Asahikawa Medical University in Japan and joined the Haase lab in 2023. He studies the role of mitochondrial electron transport in kidney physiology and pathogenesis using genetic and single cell approaches. As a graduate student, he made seminal observations regarding the interplay between SGLT2 inhibition and hypoxic signaling in diabetic nephropathy.

announcement

Haase named Fellow of the American Association for the Advancement of Science

April 2024

Volker H. Haase, M.D.

This April, the American Association for the Advancement of Science (AAAS) announced that Volker H. Haase was elected Fellow of the AAAS for his distinguished contributions to the field of experimental and translational medicine, particularly for the development and use of mouse models to study mammalian oxygen sensing in health and disease. This is a great honor for the Haase lab and a reflection of the commitment and hard work of current and former group members.

Click this link to find out more about the seven Vanderbilt faculty members who were elected to the AAAS Fellow class of 2023. “At Vanderbilt, we’re thrilled to celebrate the election of our faculty members as AAAS fellows. It not only highlights our dedication to groundbreaking research and societal impact, but also showcases the inspiration they provide to future generations of scholars,” said C. Cybele Raver, provost and vice chancellor for academic affairs. 

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 metabolism

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. > …