Effect of transforming growth factor-alpha and parathyroid hormone-related protein on phosphate transport in renal cells

Abstract

The decrease in plasma Pi concentration and in Pi tubular reabsorption that is often encountered in malignant hypercalcemia may be ascribed to a tumor-produced parathyroid hormone (PTH)-related protein. However, tumors are known to synthesize a variety of substances, among which is transforming growth factor-alpha (TGF-alpha). We investigated the effects of TGF-alpha on Na-dependent Pi transport and on the response to PTH-related protein in cultured opossum renal epithelial cells. TGF-alpha caused a concentration- and time-dependent decrease in Na-dependent Pi transport. The inhibition of Na-dependent Pi transport was detectable by 14 h of incubation and maximal by 24 h. At that time, a concentration of 10 ng/ml of TGF-alpha produced a 35 +/- 1% inhibition. This was not associated with any change in prostaglandin production. The adenosine 3',5'-cyclic monophosphate (cAMP) response to PTH-related protein, PTH, prostaglandin E2 or forskolin, but not to pertussis toxin, was diminished in cells treated with TGF-alpha for 24 h. Similar effects on Na-dependent Pi transport and cAMP production were observed in cells incubated with epidermal growth factor. The inhibition of Na-dependent Pi transport induced by either PTH-related protein or PTH was reduced after incubation with TGF-alpha. Thus two different tumoral products, TGF-alpha and PTH-related protein, are each capable of inhibiting Na-dependent Pi transport in cultured renal cells. Both peptides may also interact and influence the effects of each other on renal Pi transport.