INHIBITORS OF RENAL EPITHELIAL PHOSPHATE-TRANSPORT IN TUMOR-INDUCED OSTEOMALACIA AND UREMIA

Tumors such as sclerosing hemangiomas are sometimes associated with hy pophosphatemia and osteomalacia, both of which disappear on removal of the tumor. We identified a heat labile, 8,000-25,000 dalton, inhibito r of renal epithelial phosphate transport in supernatants of cultured sclerosing hemangioma cells obtained from a patient with oncogenic ost eomalacia and hypophosphatemia. The inhibitor does not alter glucose o r alanine transport in renal epithelial cells, and has a mechanism of cellular action distinct from that of parathyroid hormone (PTH) in tha t it inhibits phosphate transport in renal epithelia without increasin g concentrations of cyclic 3',5' adenosine monophosphate (cAMP); it's activity is not blocked by a PTH receptor antagonist. Sclerosing heman gioma cells also produce a material that cross-reacts with antisera di rected against PTH and tumor tissue sections immunostain with PTH anti bodies. We have characterized a cDNA that encodes the PTH immunoreacti ve material. In its longest open reading frame the cDNA encodes a prot ein of 381 amino acids that does not resemble PTH in its primary struc ture. Opossum kidney cells transfected with the cDNA do not produce a product that inhibits phosphate transport. Dialysates from patients wi th end-stage renal disease also contain a substance(s) that inhibits p hosphate and glucose transport in opossum kidney cells. The inhibitor( s) of phosphate uptake in dialysates is a heat labile, similar to 30,0 00 dalton substance that inhibits phosphate transport by a cAMP-indepe ndent mechanism. Determination of the structures and physiology of the se phosphate transport inhibitors is likely to yield insights into the control of phosphate homeostasis.