Genomes and Genes
REGULATIOIN OF RENAL PHOSPHATE EXCRETION AND VITAMIN D METABOLISM BY FGF 7
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
- Phosphatonins and the regulation of phosphate homeostasisTheresa 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...
- Coordination of centrosome homeostasis and DNA repair is intact in MCF-7 and disrupted in MDA-MB 231 breast cancer cellsIlie 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....
- Rearrangements and amplification of IER3 (IEX-1) represent a novel and recurrent molecular abnormality in myelodysplastic syndromesDavid 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...
- 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-kappaBChristian 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...
- Mechanisms of renal phosphate loss in liver resection-associated hypophosphatemiaOtmane 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...
- Quantification of urinary albumin by using protein cleavage and LC-MS/MSJesse 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)...
- Increased expression of secreted frizzled-related protein 4 in polycystic kidneysDaniel 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...
- Comparison between immunoturbidimetry, size-exclusion chromatography, and LC-MS to quantify urinary albuminAisha 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...
- Expression and regulation of the vitamin D receptor in the zebrafish, Danio rerioTheodore 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...
- Regulation of phosphate homeostasis by the phosphatonins and other novel mediatorsAisha 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...
- Control of renal solute excretion by enteric signals and mediatorsLeslie 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....
- A liquid chromatography-mass spectrometry method for the quantification of urinary albumin using a novel 15N-isotopically labeled albumin internal standardRavinder Singh
Clin Chem 53:540-2. 2007
- Biological activity of FGF-23 fragmentsTheresa 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...
- Hyperoxaluric nephrolithiasis is a complication of Roux-en-Y gastric bypass surgeryM 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...
- Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorptionTheresa 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...
- Increased expression of Wnt2 and SFRP4 in Tsk mouse skin: role of Wnt signaling in altered dermal fibrillin deposition and systemic sclerosisJulie 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...
- Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemiaBaozhi 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...
- The phosphatonins and the regulation of phosphate transport and vitamin D metabolismStacy 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...
- Carbohydrate metabolism and the skeleton: picking a bone with the beta-cellRajiv 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...
- Determination of serum and plasma sclerostin concentrations by enzyme-linked immunoassaysMelissa 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...
- The regulation of parathyroid hormone secretion and synthesisRajiv 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....
- Nephrolithiasis-associated bone disease: pathogenesis and treatment optionsKhashayar 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...
- Sclerostin-erbB-3 interactions: modulation of erbB-3 activity by sclerostinTheodore 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...
- Effect of phylloquinone supplementation on glucose homeostasis in humansRajiv 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...
- ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage responseP 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...
- 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...
- Sclerostin binds and regulates the activity of cysteine-rich protein 61Theodore 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...
- Production and characterization of monoclonal antibodies to human sclerostinTheodore 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...
- Pin1 regulates parathyroid hormone mRNA stabilityRajiv 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...
- Phosphate sensingRajiv 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...
- Novel mechanisms in the regulation of phosphorus homeostasisTheresa 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...
- Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapyPeter 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...