REGULATIOIN OF RENAL PHOSPHATE EXCRETION AND VITAMIN D METABOLISM BY FGF 7

Summary

Principal Investigator: RAJIV M KUMAR
Abstract: The objective of this grant proposal is to determine the physiological role and mechanism of action of a phosphaturic factor, FGF 7, and to establish its role in the pathogenesis of hypophosphatemic diseases. Our hypothesis is that FGF 7 is a potent PTN that inhibits Wnt signaling, thereby reducing renal Pi reabsorption. We will first determine whether FGF 7 has properties of a PTN. We will assess how the activity of FGF 7 is related to that of other PTNs by determining whether FGF 7 alters Wnt signaling and whether it plays a role in the pathogenesis of hypophosphatemic diseases. In aim 1, we will investigate whether FGF 7 has properties similar to those of other PTNs, FGF-23 and sFRP-4. The activity of FGF 7 will be compared with that of other PTNs such as FGF-23 and sFRP-4. We will determine if FGF 7 alters vitamin D metabolism by measuring serum 1,25(OH)2D concentrations in rats following administration of FGF 7. The effect of FGF 7 on 25(OH)D1(OH)ase activity, mRNA and protein expression will be assessed. The capacity of FGF 7 to inhibit bone mineralization will be examined. The biological effects of FGF 7 administration will be confirmed by examining the phenotype of Fgf 7 gene knockout mice. In aim 2, we will determine the nephron segment in which FGF 7 is active, and we will investigate whether FGF 7 inhibits Pi transport by reducing the activity, amount and distribution of the renal Na+Pi cotransporter. Aim 3 is designed to establish signaling pathways (receptor kinase/MAPK and Wnt/beta-catenin) involved in the inhibition of Pi uptake by FGF 7. In aim 4, we will determine if serum FGF 7 is increased in patients with TIO and XLH and in animal models of XLH. The modulation of FGF 7 by diets high or low in Pi content will be assessed to determine whether alterations in serum Pi induced by dietary changes in Pi, influence FGF 7 similarly to the hypophosphatemia in patients or animal models with renal Pi wasting. In aim 5, we will assess the relative contribution of the PTNs, FGF 7, FGF-23 and sFRP-4, to the pathogenesis of hypophosphatemia seen in animal models of renal Pi wasting. Significance: Our experiments will define a role for FGF 7 in Pi homeostasis, the regulation of vitamin D metabolism, and bone mineralization and will delineate the pathophysiologic role of FGF 7 in diseases such as TIO and XLH. The interaction between the FGF 7 and other PTNs will be clarified. Such information will significantly enhance our knowledge of mineralization processes and Pi homeostasis.
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Phosphatonins and the regulation of phosphate homeostasis
    Theresa Berndt
    Nephrology and Hypertension Research, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Annu Rev Physiol 69:341-59. 2007
  2. pmc Coordination of centrosome homeostasis and DNA repair is intact in MCF-7 and disrupted in MDA-MB 231 breast cancer cells
    Ilie D Acu
    Department of Biochemistry and Molecular Biology, Nephrology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Cancer Res 70:3320-8. 2010
  3. pmc Rearrangements and amplification of IER3 (IEX-1) represent a novel and recurrent molecular abnormality in myelodysplastic syndromes
    David P Steensma
    Mayo Clinic, Rochester, MN 55905, USA
    Cancer Res 69:7518-23. 2009
  4. pmc Ablation of gly96/immediate early gene-X1 (gly96/iex-1) aggravates DSS-induced colitis in mice: role for gly96/iex-1 in the regulation of NF-kappaB
    Christian Sina
    Institute of Clinical Molecular Biology, UKSH Campus Kiel, Kiel, Germany
    Inflamm Bowel Dis 16:320-31. 2010
  5. pmc Mechanisms of renal phosphate loss in liver resection-associated hypophosphatemia
    Otmane Nafidi
    Department of Surgery, Centre Hospitalier de l Universite de Montreal, CHUM Hôpital Saint Luc, Montreal, Quebec, Canada
    Ann Surg 249:824-7. 2009
  6. pmc Quantification of urinary albumin by using protein cleavage and LC-MS/MS
    Jesse C Seegmiller
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
    Clin Chem 55:1100-7. 2009
  7. pmc Increased expression of secreted frizzled-related protein 4 in polycystic kidneys
    Daniel Romaker
    Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, D 79106 Freiburg, Germany
    J Am Soc Nephrol 20:48-56. 2009
  8. pmc Comparison between immunoturbidimetry, size-exclusion chromatography, and LC-MS to quantify urinary albumin
    Aisha Shaikh
    Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Clin Chem 54:1504-10. 2008
  9. pmc Expression and regulation of the vitamin D receptor in the zebrafish, Danio rerio
    Theodore A Craig
    Nephrology and Hypertension Research Unit, Mayo Clinic, Rochester, Minnesota 55905, USA
    J Bone Miner Res 23:1486-96. 2008
  10. pmc Regulation of phosphate homeostasis by the phosphatonins and other novel mediators
    Aisha Shaikh
    Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic Rochester, Rochester, MN 55905, USA
    Pediatr Nephrol 23:1203-10. 2008

Scientific Experts

  • RAJIV M KUMAR
  • K Sakhaee
  • Theodore A Craig
  • Theresa Berndt
  • Aisha Shaikh
  • Stacy Sommer
  • Ravinder J Singh
  • Jesse C Seegmiller
  • Timothy S Larson
  • John C Lieske
  • Peter J Tebben
  • Melissa McNulty
  • Katrin Uhlig
  • Ilie D Acu
  • Christian Sina
  • P Pawlikowska
  • Eric J Bergstralh
  • David P Steensma
  • Xujian Li
  • Otmane Nafidi
  • Daniel Romaker
  • Bradley E Burns
  • Leslie Thomas
  • Julie Bayle
  • Baozhi Yuan
  • Ravinder Singh
  • Theresa J Berndt
  • M K Sinha
  • John W Foreman
  • Peter C Harris
  • Yanhong Wu
  • Ronald L Horst
  • Dawn S Milliner
  • Paul R Chelminski
  • Philip Rosenstiel
  • B de Laval
  • Resham Bhattacharya
  • Olga Gavrilova
  • Ricardo G Correa
  • I Leray
  • Stuart M Sprague
  • Alexander Arlt
  • S Guihard
  • Susanne Sebens Müerköster
  • Kelly Suino-Powell
  • Marie Luise Kruse
  • Jeffrey L Salisbury
  • Jeffrey S Berns
  • Heiner Schäfer
  • Ulrich R Folsch
  • Antonino B D'Assoro
  • Bryan Kestenbaum
  • Alysson R Muotri
  • Stefan Schreiber
  • Yun Niu
  • Debabrata Mukhopadhyay
  • Stanley Goldfarb
  • Emilie Midtling
  • Nicholas Rowland
  • F Porteu
  • F Rosselli
  • Steven M Mooney
  • Tieju Liu
  • Kevin J Martin
  • Mary B Leonard
  • Rhett P Ketterling
  • Johannes Donauer
  • J Jonathan Keats
  • P Leif Bergsagel
  • Kai Uwe Eckardt
  • Real W Lapointe
  • Ryan A Knudson
  • Stacy L Sommer
  • Thomas G Beito
  • Brigitta Rumberger
  • Pierre D'Amour
  • Julie C Porcher
  • Bernd Dworniczak
  • Björn Buchholz
  • Marcel Geyer
  • David R Barnidge
  • Joachim Gloy
  • H P H Neumann
  • Peter Gerke
  • Sven Teschner
  • Rafael Santana-Davila
  • Jessemy D Neiger
  • Petra Pennekamp
  • Gerd Walz
  • Robert B Jenkins

Detail Information

Publications32

  1. ncbi Phosphatonins and the regulation of phosphate homeostasis
    Theresa Berndt
    Nephrology and Hypertension Research, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Annu Rev Physiol 69:341-59. 2007
    ..This review examines the role of these factors in P(i) homeostasis in health and disease...
  2. pmc Coordination of centrosome homeostasis and DNA repair is intact in MCF-7 and disrupted in MDA-MB 231 breast cancer cells
    Ilie D Acu
    Department of Biochemistry and Molecular Biology, Nephrology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Cancer Res 70:3320-8. 2010
    ....
  3. pmc Rearrangements and amplification of IER3 (IEX-1) represent a novel and recurrent molecular abnormality in myelodysplastic syndromes
    David P Steensma
    Mayo Clinic, Rochester, MN 55905, USA
    Cancer Res 69:7518-23. 2009
    ..These data support involvement of IER3 in the pathobiology of MDS...
  4. pmc Ablation of gly96/immediate early gene-X1 (gly96/iex-1) aggravates DSS-induced colitis in mice: role for gly96/iex-1 in the regulation of NF-kappaB
    Christian Sina
    Institute of Clinical Molecular Biology, UKSH Campus Kiel, Kiel, Germany
    Inflamm Bowel Dis 16:320-31. 2010
    ..Addressing the potential role of gly96/iex-1 in the regulation of NF-kappaB in IBD, we used the dextran sodium sulfate (DSS) colitis model in mice in which the gly96/iex-1 gene had been deleted...
  5. pmc Mechanisms of renal phosphate loss in liver resection-associated hypophosphatemia
    Otmane Nafidi
    Department of Surgery, Centre Hospitalier de l Universite de Montreal, CHUM Hôpital Saint Luc, Montreal, Quebec, Canada
    Ann Surg 249:824-7. 2009
    ..To determine precisely the role of parathyroid hormone (PTH) and of phosphatonins in the genesis of posthepatectomy hypophosphatemia...
  6. pmc Quantification of urinary albumin by using protein cleavage and LC-MS/MS
    Jesse C Seegmiller
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
    Clin Chem 55:1100-7. 2009
    ..Therefore, measurement of urinary albumin must be accurate and precise. We have developed a method to quantify intact urinary albumin with a low limit of quantification (LOQ)...
  7. pmc Increased expression of secreted frizzled-related protein 4 in polycystic kidneys
    Daniel Romaker
    Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, D 79106 Freiburg, Germany
    J Am Soc Nephrol 20:48-56. 2009
    ..Taken together, these observations suggest a potential role for SFRP4 in the pathogenesis of ADPKD...
  8. pmc Comparison between immunoturbidimetry, size-exclusion chromatography, and LC-MS to quantify urinary albumin
    Aisha Shaikh
    Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Clin Chem 54:1504-10. 2008
    ..To gain insights into potential measurement biases, we systematically compared urine albumin measurements performed by LC-MS, a clinically available immunoturbidimetric assay, and size-exclusion HPLC...
  9. pmc Expression and regulation of the vitamin D receptor in the zebrafish, Danio rerio
    Theodore A Craig
    Nephrology and Hypertension Research Unit, Mayo Clinic, Rochester, Minnesota 55905, USA
    J Bone Miner Res 23:1486-96. 2008
    ..Zebrafish may serve as a useful model in which to assess the function of the VDR in diverse tissues...
  10. pmc Regulation of phosphate homeostasis by the phosphatonins and other novel mediators
    Aisha Shaikh
    Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic Rochester, Rochester, MN 55905, USA
    Pediatr Nephrol 23:1203-10. 2008
    ..Additionally, new information demonstrates that the intestine "senses" luminal concentrations of phosphate and regulates the excretion of phosphate in the kidney by elaborating novel factors that alter renal phosphate reabsorption...
  11. ncbi Control of renal solute excretion by enteric signals and mediators
    Leslie Thomas
    Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA
    J Am Soc Nephrol 19:207-12. 2008
    ....
  12. ncbi A liquid chromatography-mass spectrometry method for the quantification of urinary albumin using a novel 15N-isotopically labeled albumin internal standard
    Ravinder Singh
    Clin Chem 53:540-2. 2007
  13. pmc Biological activity of FGF-23 fragments
    Theresa J Berndt
    Department of Internal Medicine, Mayo Clinic College of Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA
    Pflugers Arch 454:615-23. 2007
    ..We conclude that carboxyl terminal fragments of FGF-23 are phosphaturic and that a short, 26-amino acid fragment of FGF-23 retains significant phosphaturic activity...
  14. ncbi Hyperoxaluric nephrolithiasis is a complication of Roux-en-Y gastric bypass surgery
    M K Sinha
    Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Kidney Int 72:100-7. 2007
    ..We conclude that hyperoxaluria is a potential complicating factor of RYGB surgery manifested as a risk for calcium oxalate stones...
  15. pmc Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption
    Theresa Berndt
    Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
    Proc Natl Acad Sci U S A 104:11085-90. 2007
    ..Our experiments demonstrate the presence of a previously unrecognized phosphate gut-renal axis that rapidly modulates renal phosphate excretion after the intestinal administration of phosphate...
  16. ncbi Increased expression of Wnt2 and SFRP4 in Tsk mouse skin: role of Wnt signaling in altered dermal fibrillin deposition and systemic sclerosis
    Julie Bayle
    Department of Medicine, Rheumatology Section, Boston University School of Medicine, Arthritis Center, Boston, Massachusetts 02118, USA
    J Invest Dermatol 128:871-81. 2008
    ..Lesional skin from SSc patients also showed large increases in SFRP4 mRNA and protein levels in the deep dermis compared to healthy skin, suggesting that the Wnt pathway might regulate skin fibrosis in SSc...
  17. pmc Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia
    Baozhi Yuan
    Department of Medicine, University of Wisconsin, GRECC, William F Middleton Veterans Administration Hospital, Madison, Wisconsin, USA
    J Clin Invest 118:722-34. 2008
    ..These data provide evidence that aberrant Phex function in osteoblasts and/or osteocytes alone is sufficient to underlie the hyp-mouse phenotype...
  18. ncbi The phosphatonins and the regulation of phosphate transport and vitamin D metabolism
    Stacy Sommer
    Nephrology and Hypertension Research, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, MS 1 120, 200 First Street SW, Rochester, MN 55905, USA
    J Steroid Biochem Mol Biol 103:497-503. 2007
    ..MEPE, however, increases circulating 1alpha,25(OH)(2)D. Circulating or local concentrations of these peptides/proteins may regulate 25-hydroxyvitamin D 1alpha-hydroxylase activity in renal tissues under physiologic circumstances...
  19. pmc Carbohydrate metabolism and the skeleton: picking a bone with the beta-cell
    Rajiv Kumar
    Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
    J Clin Endocrinol Metab 96:1269-71. 2011
    ..More extensive and detailed experiments in humans are needed to definitively establish the role of undercarboxylated osteocalcin in human carbohydrate metabolism...
  20. pmc Determination of serum and plasma sclerostin concentrations by enzyme-linked immunoassays
    Melissa McNulty
    Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    J Clin Endocrinol Metab 96:E1159-62. 2011
    ..We determined sclerostin concentrations in serum and plasma using two commercially available ELISA...
  21. ncbi The regulation of parathyroid hormone secretion and synthesis
    Rajiv Kumar
    Division of Nephrology and Hypertension, Departments of Medicine, Biochemistry and Molecular Biology, Mayo Clinic and Foundation, 200 1 Street SW, Rochester, MN 55905, USA
    J Am Soc Nephrol 22:216-24. 2011
    ....
  22. pmc Nephrolithiasis-associated bone disease: pathogenesis and treatment options
    Khashayar Sakhaee
    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390 8885, USA
    Kidney Int 79:393-403. 2011
    ..This manuscript reviews the epidemiology, pathophysiology, and potential treatments of bone disease in patients with nephrolithiasis...
  23. pmc Sclerostin-erbB-3 interactions: modulation of erbB-3 activity by sclerostin
    Theodore A Craig
    Nephrology and Hypertension Research, Department of Internal Medicine, MS 1 120, Mayo Clinic, 200 1st St, Southwest, Rochester, MN 55905, USA
    Biochem Biophys Res Commun 402:421-4. 2010
    ..The data demonstrate that sclerostin functions in part, by modulating the activity of erbB-3...
  24. pmc Effect of phylloquinone supplementation on glucose homeostasis in humans
    Rajiv Kumar
    Nephrology Research Unit, Divisions of Nephrology and Hypertension and the Division of Endocrinology and Metabolism, Department of Medicine, Mayo Clinic, Rochester, MN, USA
    Am J Clin Nutr 92:1528-32. 2010
    ..Under-γ-carboxylated osteocalcin (ucOC) increases insulin secretion and decreases glucose concentrations in mice...
  25. pmc ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage response
    P Pawlikowska
    INSERM U, Institut Cochin, Paris, France
    Cell Death Differ 17:1739-50. 2010
    ..Deciphering the pathways involved in IEX-1 degradation should lead to the discovery of new therapeutic targets to increase sensitivity of tumor cells to chemotherapy...
  26. ncbi KDOQI US commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD-Mineral and Bone Disorder (CKD-MBD)
    Katrin Uhlig
    Tufts Medical Center, Tufts University School of Medicine, Boston MA, USA
    Am J Kidney Dis 55:773-99. 2010
    ..The lack of definitive clinical outcome trials explains why most recommendations are not of level 1 but of level 2 strength, which means weak or discretionary recommendations. Suggestions for future research highlight priority areas...
  27. pmc Sclerostin binds and regulates the activity of cysteine-rich protein 61
    Theodore A Craig
    Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
    Biochem Biophys Res Commun 392:36-40. 2010
    ..The data show that sclerostin binds to and influences the activity of Cyr61...
  28. pmc Production and characterization of monoclonal antibodies to human sclerostin
    Theodore A Craig
    Nephrology Research, Department of Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
    Hybridoma (Larchmt) 28:377-81. 2009
    ..The antibodies are potentially useful agents that can be used for modulating sclerostin bioactivity...
  29. pmc Pin1 regulates parathyroid hormone mRNA stability
    Rajiv Kumar
    Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA
    J Clin Invest 119:2887-91. 2009
    ..This work suggests new ways by which to regulate PTH synthesis in secondary hyperparathyroidism...
  30. pmc Phosphate sensing
    Rajiv Kumar
    Departments of Medicine, Biochemistry and Molecular Biology, Division of Nephrology and Hypertension, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA
    Curr Opin Nephrol Hypertens 18:281-4. 2009
    ..To discuss findings suggesting the presence of a phosphate-sensing mechanism in the various organs and the presence of a novel intestinal effector that alters renal phosphate excretion after the ingestion of a phosphate-containing meal...
  31. pmc Novel mechanisms in the regulation of phosphorus homeostasis
    Theresa Berndt
    Department of Medicine, Nephrology Research, Mayo Clinic and Foundation, Rochester, Minnesota, USA
    Physiology (Bethesda) 24:17-25. 2009
    ..In this review, we discuss how organisms sense changes in phosphate concentrations and how changes in hormonal factors result in the conservation or excretion of phosphorus...
  32. pmc Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy
    Peter J Tebben
    Mercy Healthcare, Edmond, OK 73142, USA
    J Clin Endocrinol Metab 97:E423-7. 2012
    ..Treatment of hypercalcemia associated with CYP24A1 gene mutations has not been described...