targeting the hif oxygen-sensing pathway for anemia therapynephro-necker.org/pdf/2017/05.pdf ·...
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Rein et Oxygène
Targeting the HIF Oxygen-Sensing Pathway for
Anemia Therapy
Volker H. Haase
The Krick-Brooks Chair in Nephrology Departments of Medicine, Cancer Biology,
Molecular Physiology and Biophysics Vanderbilt University, Nashville
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Outline
Brief overview of the HIF pathway
Cellular and molecular regulation of erythropoietin
(EPO) production in the kidney
Application to renal anemia: Inhibition of HIF PHDs
stimulates EPO production in the kidney and liver
Application to renal anemia: HIF and iron metabolism
Application to renal anemia: HIF-prolyl hydroxylase
(HIF-PHIs) inhibitors in clinical trials
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Physiologic Responses to Hypoxia
and Discovery of the HIF-PHD Pathway
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Activation of hypoxic signaling occurs when tissues experience
a discrepancy between O2 demand and supply
Exercise Tumor
High altitude
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Time Course of Selected Physiologic Responses to Hypoxia
Andrew M. Luks J Appl Physiol 2015;118:509-519
©2015 by American Physiological Society
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Anglo-American Expedition to Pikes Peak, CO Aug. 1911, 14147 ft (JS Haldane, CG Douglas, Y Henderson, EC Schneider, and M Fitzgerald)
Pioneers of High Altitude Medicine
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HIF controls the Hypoxic Induction of EPO
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• Wang, G.L. and Semenza, G.L. (1995). Purification and characterization of hypoxia-inducible factor
1. J. Biol. Chem. 270, 1230-1237.
• Wang, G.L., Jiang, B.-H., Rue, E.A., and Semenza, G. L. (1995). Hypoxia-inducible factor 1 is a
basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci.
USA. 92, 5510-5514.
• Forsythe, J.A., Jiang, B.-H., Iyer, N.V., Agani, F., Leung, S.W., Koos, R.D., and Semenza, G.L. (1996).
Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.
Mol. Cell. Biol. 16, 4604-4613.
• Maxwell, P.H., Pugh, C.W., and Ratcliffe, P.J. (1993). Inducible operation of the erythropoietin
3' enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism. Proc.
Natl. Acad. Sci. USA. 90, 2423-2427.
• Maxwell, P.H. et al. (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors
for oxygen-dependent proteolysis. Nature. 399, 271-275.
• Jaakkola, P. et al. (2001). Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by
O2-regulated prolyl hydroxylation. Science. 292, 468-472
• Epstein, A.C.R. et al.. (2001). C. elegans EGL-9 and mammalian homologs define a family of
dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 107, 43-54.
• Iliopoulos, O., Levy, A.P., Jiang, C., Kaelin, W.G., Jr., and Goldberg, M.A. (1996). Negative regulation
of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc. Natl. Acad. Sci. USA. 93,
10595-10599.
• Ohh, M., Park, C.W., Ivan, M., Hoffman, M.A., Kim, T.-Y., Huang, L.E., Chau, V., Pavletich, N., and
Kaelin, W.G., Jr. (2000). Ubiquitination of hypoxia-inducible factor requires direct binding to the β-
domain of the von Hippel-Lindau protein. Nat. Cell Biol. 2, 423-427.
• Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J.M., Lane, W.S., and
Kaelin, W.G., Jr. (2001). HIF targeted for VHL-mediated destruction by proline hydroxylation:
implications for O2 sensing. Science. 292, 464-468
Discovery of the HIF-Oxygen Sensing Pathway
Gregg L. Semenza
Johns Hopkins
Peter J. Ratcliffe
Oxford
William G. Kaelin, Jr.
Harvard
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Transcriptional Targets of HIF
HIF
Vasculogenesis/Angiogenesis Heme oxygenase-2 NOS-2, PAI - I VEGF, VEGF-R (FLT-1)
Iron metabolism /Erythropoiesis Ceruloplasmin EPO (HIF-2 > HIF-1) Transferrin Transferrin R
Metabolism: Glycolysis (HIF-1) Fat metabolism (HIF-2) Adenylate kinase-3 Carbonic anhydrase-9 Glut-1 and -3 Glycolytic enzymes (Hexokinase, LDH,PGK, etc.) Leptin
Proliferation/Cell survival Cyclin G2, EPO, Heme oxygenase 1 IGF-2, IGFBP1, -2, -3 NOS-2, NIP-3, p21 TGF-b3, VEGF, WT1 Indirect: c-Myc
HYPOXIA via
ECM production/Cell migration CxCR4, c-met, CTGF, PAI-1, Procollagen prolyl hydroxylase-a1
Epithelial Barrier Function ITF, MDR-1, CD73
Transcription factors Ets-1, DEC-1/Stra13
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Regulation of HIF-α Stability
Angiotensin II
Non-hypoxic
stimuli:
Interleukin1,
TNF-a, Growth
factors
HIF: hypoxia-inducible factor
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The Hydroxylation Reaction
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2OG-dependent Dioxygenases
- at least 60 in mammals -
Loenarz and Schofield, Nature Chemical Biology, 2008 PHD1, PHD2, PHD3
FIH
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Cellular and Molecular Regulation of
EPO Production in the Kidney
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GATA-2/3 (5’-TGATAA-3’)
Hypoxic Regulation of EPO: HIF-2
EPO: erythropoietin; HIF: hypoxia-inducible factor.
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The Number of Renal EPC
Determines EPO Output
EPC: erythropoietin-producing cell; EPO: erythropoietin; HIF: hypoxia-inducible factor; PHD: prolyl-4-hydroxylase domain.
Kidney at baseline:
small EPC pool size
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Erythrocytosis Syndromes Resulting from Genetic Defects in HIF-2 Oxygen Sensing
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HIF-2 and PHD2 mutations confer protection from high altitude-associated illnesses
Hemoglobin concentration of high-altitude
Tibetans and Bolivian Aymara. Cynthia Beall et
al. Am J Phys Anthropol 1998, 106: 385-400.
Genetic Evidence for High-Altitude Adaptation
in Tibet. Tatum S. Simonson et al. Science 2010,
329: 72-75.
Sequencing of 50 human exomes reveals
adaptation to high altitude. Xin Yi et al. Science.
2010, 329: 75-8.
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Application to Renal Anemia I:
Inhibition of HIF-PHDs Stimulates EPO
Synthesis in Kidney and Liver
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200 X
EPO Neg. Ctl
400 X 200 X
EPO
Phd2-/- Phd2-/- Phd2-/-
Cre-/- Cre-/- Cre-/-
Targeting Phd2 in Peritubular Interstitial Cells
EPO: erythropoietin; PHD: prolyl-4-hydroxylase domain.
Kobayashi H, et al. J Clin Invest. 2016;126(5):1926-1938.
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Targeting Phd2 in Renal Interstitial Cells
Co: control; EPO: erythropoietin; Hb: hemoglobin; Hct: hematocrit; PHD: prolyl-4-hydroxylase domain; RBC: red blood cells;
Retic: reticulocyte; VEGF: vascular endothelial growth factor.
Kobayashi H, et al. J Clin Invest. 2016;126(5):1926-1938.
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Distinct Interstitial Cell Populations
Regulate Renal EPO Output
EPO: erythropoietin; PHD: prolyl-4-hydroxylase domain; REPC: renal EPO-producing cell.
Kobayashi H, et al. J Clin Invest. 2016;126(5):1926-1938.
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The Liver as a Source of EPO:
Role of Individual PHDs
EPO: erythropoietin; PHD: prolyl-4-hydroxylase domain.
Tojo Y, et al. Mol Cell Biol. 2015;35(15):2658-2672.
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The hypoxic induction of EPO in the kidney and liver is HIF-
2-dependent
Inactivation of PHD2 alone is sufficient to stimulate the
production of renal EPO
There are at least two distinct populations of EPO-
producing cells in the kidney that differ in their regulation
of HIF-2 activity and EPO production
Inactivation of at least 2 PHD enzymes in the liver is
required to stimulate erythropoiesis
Key Points
EPO: erythropoietin; HIF: hypoxia-inducible factor; PHD: prolyl-4-hydroxylase domain.
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Application to Renal Anemia II:
HIF and iron metabolism
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Pathogenesis of Renal Anemia
EPO: erythropoietin.
Koury MJ, Haase VH. Nat Rev Nephrol. 2015;11(7):394-410.
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REPC in Renal Injury
CKD: chronic kidney disease; EPO: erythropoietin; REPC: renal EPO-producing cell.
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HIF in Iron Metabolism
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PHD inhibition stimulates both renal and hepatic EPO
production
Myofibroblast differentiation reduces EPO producing capacity
in the kidney
PHD therapy in CKD: maintenance of EPO-producing
capacity in interstitial cells that already produce EPO versus
conversion of non-EPO producing interstitial cells into EPO-
producing cells
HIF activation enhances iron uptake and utilization. HIF
effects on hepcidin production appear to be indirect
Key Points
CKD: chronic kidney disease; EPO: erythropoietin; HIF: hypoxia-inducible factor; PHD: prolyl-4-hydroxylase domain.
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Application to Renal Anemia III:
HIF-PHD Inhibitors: Clinical trials
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The Hydroxylation Reaction
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HIF-Prolyl Hydroxylase Inhibition Beyond erythropoiesis: what to look for
VEGF
Metabolic effects (glucose, cholesterol, fat
metabolism, uric acid, FGF 23)
Blood pressure, hemodynamics
effects on kidney disease progression
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PHD2 vs. PHD1 vs. PHD3 - IC50 profiles
HIF PHDs have other hydroxylation targets
effects on other dioxygenases (FIH, Jmjds, others)
tissue distribution
Biological effects in kidney vs. liver vs. other tissues
(bone marrow, gastrointestinal tract)
Genetic variations
HIF-Prolyl Hydroxylase Inhibition How to evaluate compound actions
pharmacodynamic and pharmacokinetic considerations
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Haase V.H.; Hemodialysis International, in press
HIF-Prolyl Hydroxylase Inhibition
Overview of compounds
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HIF-PHIs
Chemical structure
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Haase V.H.; Hemodialysis International, in press
HIF-Prolyl Hydroxylase Inhibition
Clinical experience from phase 2 trials
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HIF-PHIs have been effective in stimulating erythropoiesis
To date HIF-PHIs have been well tolerated in phase 2 trials
Some of the compounds have clinical effects beyond
erythropoeisis
Long term safety evaluations are pending
The effects on CKD progression are not known
HIF-Prolyl Hydroxylase Inhibition
Summary