Growth factors and renal regulation of phosphate transport

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Abstract
During the development of vertebrates, the extracellular concentration of inorganic phosphate (Pi) is maintained at a higher level than during adult life. This elevation is probably essential for both cellular growth and mineralization of the skeleton. A high tubular Pi transport capacity (maxTRPi/GFR) and a high plasma level of 1,25-dihydroxyvitamin D3 are considered to play a major role in the high Pi retention observed during growth. Experimental studies have shown that the high maxTRPi/GFR observed in growing young compared with adult individuals is not associated with differences in other renal functions, suggesting the existence of a selective homeostatic process. Growth hormone (GH) had no direct effect on renal Pi reabsorption, indicating that GH stimulation of renal Pi transport in various physiological and pathophysiological conditions is induced by insulin-like growth factor-1 (IGF-1), the mediator of the anabolic effects of GH. In hypophysectomized rats, administration of IGF-1 mimicked the stimulatory effects of GH on maxTRPi per milliliter glomerular filtrate and on plasma 1,25-dihydroxyvitamin D3. As for GH, the change in maxTRPi per milliliter glomerular filtrate induced by IGF-1 was mediated by a parathyroid hormone-independent mechanism and was selectively expressed at the level of the luminal membrane of proximal tubules. These observations are evidence that IGF-1 mediates the effect of GH on the renal handling of Pi and production of 1,25-dihydroxyvitamin D3 and might play a significant role in the control of Pi metabolism during growth. Recent observations suggest that other growth factors might be involved in the regulation of tubular Pi transport. Epidermal growth factor (EGF) was found to selectively enhance Pi transport in the rabbit proximal convoluted tubule. The cellular mechanism responsible for the stimulation of Pi transport by growth factors has been recently investigated in cultured kidney cells. Since both IGF-1 and EGF activate receptors with intrinsic tyrosine kinase activity, the changes in both Pi transport and tyrosine phosphorylation were determined in response to orthovanadate, an insulin-like agent, and genistein, a selective inhibitor of tyrosine kinase. The change in Pi transport across the apical membrane of cultured kidney cells was highly correlated with alterations in tyrosine kinase activity determined in isolated plasma membranes. These observations strongly suggest that IGF-1 plays a significant role in the control of Pi homeostasis during growth. They also provide good evidence that protein tyrosine phosphorylation mediates the stimulatory effect of Pi transport induced by mitogenic factors such as IGF-1 and EGF.