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Dr. Haase's research lab's publication published in Kidney International

December 29th 2017

Dr. Volker Haase, The Krick-Brooks Chair in Nephrology, Professor of Medicine, Cancer Biology, Molecular Physiology and Biophysics, Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center

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Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development.

Kobayashi H, Liu J, Urrutia AA, Burmakin M, Ishii K, Rajan M, Davidoff O, Saifudeen Z, Haase VH

Abstract

Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.

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Dr. Haase's research focus:

LABORATORY of OXYGEN METABOLISM

The Haase research group has long-standing expertise in the molecular, genetic and metabolic analysis of mammalian hypoxia and hypoxia-inducible factor (HIF)-mediated responses, as well as HIF-related transcriptional biology. Hypoxia-Inducible Factors HIF-1 and HIF-2 are oxygen-sensitive basic helix-loop-helix transcription factors that regulate biological processes, which facilitate both oxygen delivery and cellular adaptation to oxygen deprivation. HIFs consist of an oxygen-sensitive alpha-subunit, HIF-alpha, and a constitutively expressed beta-subunit, HIF-beta, and regulate the expression of genes that are involved in energy metabolism, angiogenesis, erythropoiesis and iron metabolism, cell proliferation, apoptosis and other biological processes.


HIF activity is controlled by prolyl-4-hydroxylase domain (PHD) enzymes, which function as oxygen sensors that target the a-subunit of HIF for hydroxylation and subsequent proteasomal degradation via the von Hippel-Lindau (VHL)-E3 ubiquitin ligase. These enzymes represent excellent drug targets and several compounds are currently in clinical trials for the treatment of renal anemia (Koury and Haase, Nat Rev Nephrol, 2015).
Initially, the Haase research program started with the generation of the first mouse model for VHL disease, which reproduces clinical manifestations of the disease, such as renal cysts, hemangiomas and polycythemia. As part of this effort, the laboratory has established specific roles for HIF-1 and HIF-2 in the pathogenesis of VHL-associated liver hemangiomas, in the hypoxic induction of hepatic and renal erythropoietin and in the regulation of glucose and fatty acid metabolism.
A main focus of the laboratory is on understanding the molecular and cellular basis of hypoxia responses in the adult kidney and in kidney development. As part of this effort the laboratory have spearheaded studies that established novel molecular links between hypoxia, HIF signaling and the progression of chronic kidney disease. The lab furthermore have spearheaded studies that aim at defining the interplay between alterations in energy metabolism, cellular differentiation and function, cell-cell interactions, inflammation and tissue repair mechanisms. For this the laboratory has developed novel technology that permits spatial high-resolution imaging of metabolites in tissue sections.


Another major research focus is on the role of HIF in the regulation of EPO synthesis in kidney and liver as well as iron metabolism. The Haase laboratory has generated several genetic models of polycythemia and anemia and has contributed to defining HIF’s role in iron metabolism and to the development of drugs (HIF stabilizers) that are currently in clinical trial for the treatment of renal anemia. Specifically, the group has identified HIF-2 as the key regulator of renal EPO synthesis and established that HIF coordinates erythropoiesis with iron metabolism by directly regulating iron uptake and release