Inhibitors of renal epithelial phosphate transport in tumor-induced osteomalacia and uremia.
Tumors such as sclerosing hemangiomas are sometimes associated with hypophosphatemia and osteomalacia, both of which disappear on removal of the tumor. We identified a heat labile, 8,000-25,000 dalton, inhibitor of renal epithelial phosphate transport in supernatants of cultured sclerosing hemangioma cells obtained from a patient with oncogenic osteomalacia and hypophosphatemia. The inhibitor does not alter glucose or alanine transport in renal epithelial cells, and has a mechanism of cellular action distinct from that of parathyroid hormone (PTH) in that it inhibits phosphate transport in renal epithelia without increasing concentrations of cyclic 3',5' adenosine monophosphate (cAMP); it's activity is not blocked by a PTH receptor antagonist. Sclerosing hemangioma cells also produce a material that cross-reacts with antisera directed against PTH and tumor tissue sections immunostain with PTH antibodies. We have characterized a cDNA that encodes the PTH immunoreactive material. In its longest open reading frame the cDNA encodes a protein of 381 amino acids that does not resemble PTH in its primary structure. Opossum kidney cells transfected with the cDNA do not produce a product that inhibits phosphate transport. Dialysates from patients with end-stage renal disease also contain a substance(s) that inhibits phosphate and glucose transport in opossum kidney cells. The inhibitor(s) of phosphate uptake in dialysates is a heat labile, approximately 30,000 dalton substance that inhibits phosphate transport by a cAMP-independent mechanism. Determination of the structures and physiology of these phosphate transport inhibitors is likely to yield insights into the control of phosphate homeostasis.
Kumar
R
R
Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Haugen
J D
JD
Wieben
E D
ED
Londowski
J M
JM
Cai
Q
Q
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D003429:Cross Reactions; D000242:Cyclic AMP / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006391:Hemangioma / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D009893:Opossums; D010018:Osteomalacia / Q000209:etiology / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000276:immunology; D010710:Phosphates / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D012964:Sodium / Q000378:metabolism; D014511:Uremia / Q000209:etiology / Q000378:metabolism*
C099045:HEM-1 phosphate transport inhibitor; D009363:Neoplasm Proteins; D010281:Parathyroid Hormone; D010710:Phosphates; D011994:Recombinant Proteins; D012964:Sodium; D000242:Cyclic AMP