Involvement of hypoxia-inducible transcription factors in polycystic kidney disease.

In polycystic kidney disease (PKD), erythropoietin (EPO) production and interstitial vascularization are increased compared with other kidney diseases. EPO and several angiogenic factors are controlled by hypoxia-inducible transcription factors (HIFs), which are composed of a constitutive beta-subunit and two alternative alpha-subunits (HIF-1alpha, HIF-2alpha). We hypothesized that cyst expansion may result in pericystic hypoxia and consecutive up-regulation of HIF and thus examined the expression of HIF-alpha and HIF target genes in human PKD and in a rodent PKD model. HIF-1alpha and HIF-2alpha were found to be up-regulated in cyst epithelium and cells of cyst walls, respectively. The distinct expression pattern of the HIF-alpha isoforms closely resembles the respective pattern in normal kidneys under systemic hypoxia. Pimonidazole staining, a marker for tissue hypoxia, confirmed the existence of regional hypoxia in polycystic kidneys. Immunohistochemistry for selected target genes implicated a role for HIF-1alpha in vascular endothelial growth factor and Glut-1 activation and HIF-2alpha in endoglin and EPO stimulation. Polycystin-deficient cells showed physiological, oxygen-dependent HIF-alpha modulation, excluding a direct influence of polycystin deficiency on HIF-alpha regulation. In conclusion, HIF accumulation in human and rat PKD seems to be responsible for increased EPO production and pericystic hypervascularity and may have an impact on progression of PKD.

[1]  J. Wen,et al.  Evidence of angiogenesis and microvascular regression in autosomal-dominant polycystic kidney disease kidneys: a corrosion cast study. , 2006, Kidney international.

[2]  M. Tran,et al.  Formation of primary cilia in the renal epithelium is regulated by the von Hippel-Lindau tumor suppressor protein. , 2006, Journal of the American Society of Nephrology : JASN.

[3]  A. Novick,et al.  The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[4]  V. Haase,et al.  The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. , 2006, Kidney international.

[5]  E. Rankin,et al.  Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. , 2006, Cancer research.

[6]  P. Wahl,et al.  Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). , 2006, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[7]  K. Eckardt,et al.  Expression of hypoxia-inducible transcription factors in developing human and rat kidneys. , 2006, Kidney international.

[8]  I. Mellinghoff,et al.  Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer , 2006, Nature Medicine.

[9]  B. Yoder,et al.  An incredible decade for the primary cilium: a look at a once-forgotten organelle. , 2005, American journal of physiology. Renal physiology.

[10]  S. Oldham,et al.  The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-α/Sima , 2005, Journal of Cell Science.

[11]  P. Maxwell.  Hypoxia‐inducible factor as a physiological regulator , 2005, Experimental physiology.

[12]  P. Maxwell.  The HIF pathway in cancer. , 2005, Seminars in cell & developmental biology.

[13]  M. Dewhirst,et al.  Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. , 2005, Cancer cell.

[14]  P. Reinke,et al.  Up-regulation of HIF in experimental acute renal failure: evidence for a protective transcriptional response to hypoxia. , 2005, Kidney international.

[15]  Y. Tao,et al.  Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. , 2004, Journal of the American Society of Nephrology : JASN.

[16]  J. García Rodríguez,et al.  [Polycystic Kidney Disease]. , 2005, Actas urologicas espanolas.

[17]  V. Erdmann,et al.  Differentiating the functional role of hypoxia‐inducible factor (HIF)‐1α and HIF‐2α (EPAS‐1) by the use of RNA interference: erythropoietin is a HIF‐2α target gene in Hep3B and Kelly cells , 2004 .

[18]  D. Allen,et al.  Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. , 2004, Journal of the American Society of Nephrology : JASN.

[19]  G. Macpherson,et al.  Small Molecule-Mediated Anti-Cancer Therapy via Hypoxia Inducible Factor-1 Blockade , 2004, Cancer biology & therapy.

[20]  G. Melillo.  HIF-1: A Target For Cancer, Ischemia and Inflammation—Too Good to be True? , 2004, Cell cycle.

[21]  V. Erdmann,et al.  Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells. , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  Benjamin D Cowley.  Recent advances in understanding the pathogenesis of polycystic kidney disease: therapeutic implications. , 2004, Drugs.

[23]  Christian Frelin,et al.  Hypoxia Up-regulates Prolyl Hydroxylase Activity , 2003, Journal of Biological Chemistry.

[24]  K. Eckardt,et al.  Cellular responses to hypoxia after renal segmental infarction. , 2003, Kidney international.

[25]  O. Ibraghimov-Beskrovnaya,et al.  Functional analysis of PKD1 transgenic lines reveals a direct role for polycystin-1 in mediating cell-cell adhesion. , 2003, Journal of the American Society of Nephrology : JASN.

[26]  Jens Overgaard,et al.  Measurements of hypoxia using pimonidazole and polarographic oxygen-sensitive electrodes in human cervix carcinomas. , 2003, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[27]  Kai-Uwe Eckardt,et al.  The FASEB Journal express article 10.1096/fj.02-0445fje. Published online December 17, 2002. Widespread, hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs , 2022 .

[28]  P. Maxwell,et al.  HIF and oxygen sensing; as important to life as the air we breathe? , 2003, Annals of medicine.

[29]  E. Abderrahim,et al.  Anemia and end-stage renal disease in the developing world. , 2002, Artificial organs.

[30]  Y. Sugisaki,et al.  Peritubular capillary regression during the progression of experimental obstructive nephropathy. , 2002, Journal of the American Society of Nephrology.

[31]  Charles C Wykoff,et al.  HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. , 2002, Cancer cell.

[32]  Kai-Uwe Eckardt,et al.  Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. , 2002, Journal of the American Society of Nephrology : JASN.

[33]  L. Agodoa,et al.  Polycystic kidney disease at end-stage renal disease in the United States: patient characteristics and survival. , 2002, Clinical nephrology.

[34]  K. Holubec,et al.  Angiogenesis in autosomal-dominant polycystic kidney disease. , 2001, Kidney international.

[35]  J. Hughes,et al.  Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1. , 2001, Journal of the American Society of Nephrology : JASN.

[36]  H. Kitamura,et al.  Peritubular capillary injury during the progression of experimental glomerulonephritis in rats. , 2000, Journal of the American Society of Nephrology : JASN.

[37]  W. Jelkmann,et al.  Interleukin-1β and Tumor Necrosis Factor- Stimulate DNA Binding of Hypoxia-Inducible Factor-1 , 1999 .

[38]  C. Wykoff,et al.  The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis , 1999, Nature.

[39]  W. Jelkmann,et al.  Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1. , 1999, Blood.

[40]  D. Ribatti,et al.  Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. , 1999, Blood.

[41]  A. Harris,et al.  Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha. , 1998, Blood.

[42]  S. Richard,et al.  Renal involvement in von Hippel-Lindau disease. , 1996, Kidney international.

[43]  K. Plate,et al.  Expression of vascular endothelial growth factor and its receptors in human renal ontogenesis and in adult kidney. , 1995, The American journal of physiology.

[44]  F. Brosius,et al.  Immunogold localization of high-affinity glucose transporter isoforms in normal rat kidney. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[45]  N. Gretz,et al.  Characterization of the Han:SPRD rat model for hereditary polycystic kidney disease. , 1994, Kidney international.

[46]  F. Deerberg,et al.  A new rat model for polycystic kidney disease of humans. , 1990, Transplantation proceedings.

[47]  H. Scholz,et al.  Erythropoietin in polycystic kidneys. , 1989, The Journal of clinical investigation.

[48]  M. Miller,et al.  Serum immunoreactive erythropoietin levels in patients with polycystic kidney disease as compared with other hemodialysis patients. , 1985, Nephron.