Research News

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. This was associated with abnormal mitochondrial morphology, a reduction in oxygen consumption and increased glycolytic flux. Furthermore, we found that TFAM expression was reduced in murine and human polycystic kidneys, which was accompanied by mitochondrial depletion. Thus, our data suggest that dysregulation of TFAM expression and mitochondrial depletion are molecular features of kidney cystic disease that may contribute to its pathogenesis.

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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. At week six tubular injury markers normalized but with patchy collagen I and interstitial fibrosis. Pimonidazole staining, a hypoxia marker, was increased by folic acid treatment compared to vehicle while dimethyloxalylglycine stimulated HIF-2α expression and attenuated tubulointerstitial hypoxia. The hematocrit was increased by dimethyloxalylglycine along with downstream effectors of HIF. Tubular epithelial cell injury, inflammation and interstitial fibrosis were improved after dimethyloxalylglycine, with further reduced mortality, interstitial fibrosis, and glomerulosclerosis induced by specific podocyte injury. Thus, our findings indicate that hypoxia contributes to tubular injury and consequent sensitization of glomeruli to injury. Hence, restoring HIFs may blunt this adverse crosstalk of tubules to glomeruli.

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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

Phd inactivation in brain pericytes

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

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

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Congratulations to our collaborator Mark Boothby on the acceptance of his PNAS paper

April 2019

Hypoxia-inducible factors in CD4+ T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity

T cell help in humoral immunity includes interactions of B cells with activated extrafollicular CD4+ and follicular T helper (Tfh) cells. Each can promote antibody responses but Tfh cells play critical roles during germinal center (GC) reactions. After restimulation of their antigen receptor (TCR) by B cells, helper T cells act on B cells via CD40 ligand and secreted cytokines that guide Ig class switching. Hypoxia is a normal feature of GC, raising questions about molecular mechanisms governing the relationship between hypoxia response mechanisms and T cell help to antibody responses. Hypoxia-inducible factors (HIF) are prominent among mechanisms that mediate cellular responses to limited oxygen but also are induced by lymphocyte activation. We now show that loss of HIF-1α or of both HIF-1α and HIF-2α in CD4+ T cells compromised essential functions in help during antibody responses. HIF-1α depletion from CD4+ T cells reduced frequencies of antigen-specific GC B cells, Tfh cells, and overall antigen-specific Ab after immunization with sheep red blood cells. Compound deficiency of HIF-1α and HIF-2α led to humoral defects after hapten-carrier immunization. Further, HIF promoted CD40L expression while restraining the FoxP3-positive CD4+ cells in the CXCR5+ follicular regulatory population. Glycolysis increases T helper cytokine expression, and HIF promoted glycolysis in T helper cells via TCR or cytokine stimulation, as well as their production of cytokines that direct antibody class switching. Indeed, IFN-γ elaboration by HIF-deficient in vivo-generated Tfh cells was impaired. Collectively, the results indicate that HIF transcription factors are vital components of the mechanisms of help during humoral responses.

Phase II study on HIF-PHI vadadustat in hemodialysis patients

Effects of Vadadustat on Hemoglobin Concentrations in Patients Receiving Hemodialysis Previously Treated with Erythropoiesis Stimulating Agents

April 2018

Erythropoiesis-stimulating agents (ESAs) can correct anemia in chronic kidney disease (CKD) but are associated with increased risks of cardiovascular events. Vadadustat, an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain (HIF-PHD) dioxygenases, is an oral investigational agent in development for the treatment of anemia in patients with CKD.

In a 16-week, open-label, multicenter, Phase 2 trial, Haase and colleagues evaluated vadadustat in 94 patients receiving maintenance hemodialysis previously maintained on ESA therapy. Patients were converted to vadadustat and assigned to a prospective dose cohort: 300 mg daily, 450 mg daily, or 450 mg thrice weekly. The primary endpoints were the mean hemoglobin change from baseline to mid-trial and from baseline to end-of-trial.

No significant changes in hemoglobin concentrations were observed for the two time points in any of the three treatment groups. Hemoglobin concentrations remained stable after conversion from ESA therapy for the duration of the trial, with a single excursion >13 g/dL. Plasma concentrations of vadadustat or its metabolites were not affected by hemodialysis.

Post-hoc analyses found no association between the final vadadustat dose and achieved hemoglobin, baseline hepcidin, C-reactive protein, or previous ESA dose. The overall incidence of adverse events (AEs) was comparable across treatment groups. No deaths occurred during the study. No serious AEs were attributed to vadadustat.

In summary this new study concluded that Vadadustat maintained hemoglobin concentrations in patients on hemodialysis previously receiving ESA therapy.

click here for link to erythropoiesis, iron metabolism and renal anemia

click here to access media files on renal anemia

Haase lab identifies a new role for HIF-PHD oxygen sensors in kidney development

December 2017

Insufficient oxygenation during pregnancy negatively influences kidney development, which predisposes to chronic kidney disease at later stages in life. Kobayashi et al. demonstrate that deletion of HIF prolyl-hydroxylase (PHD) 2 and 3, in FoxD1 lineage cells reduces kidney size and inhibits nephrogenesis in mice. Temporo-spatial expression pattern and studies on additional knockouts suggest the involvement of hypoxia-inducible factor (HIF)-2. More ...

click here to read the associated commentary in Kidney International

click here for link to research themes in the Haase lab