The experiments outlined in this proposal examine the interaction between 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3)and polypeptide growth factors in both developing and mature kidney. The calciotropic hormone, 1,25-(OH)2D3, has been found to be a potent regulator of cell growth and differentiation. Besides containing the enzyme (1alpha-hydroxylase) responsible for the synthesis of 1,25-(OH)2D3, the kidney both produces and is a target for several polypeptide growth factors which have paracrine activity and are required for both fetal renal development and renal growth. In bone, 1,25-(OH)2D3 alters the expression of these growth factors. Growth factors, IGF I in particular, may themselves regulate the production of 1,25(OH)2D3. Studies outlined in this application address the following issues: 1) The effect of 1,25-(OH)2D3 on the expression of polypeptide growth factors and on subsequent development of the metanephros; 2) The ontogeny of the vitamin D receptor (VDR), which mediates the activity of 1,25-(OH)2D3, and of the renal 1alpha-hydroxylase. 3) The effect of polypeptide growth factors on the 1alpha-hydroxylase; 3) The role of 1,25(OH)2D3 in modulating compensatory renal hypertrophy following uninephrectomy; 4) The effects of IGF I on Pi handling and vitamin D metabolism will be studied in X-linked hypophosphatemic rickets using the murine model, the Hyp mouse. This disease is characterized by low renal tubular reabsorption of phosphate and an abnormal 1alpha-hydroxylase response to hypophosphatemia. IGF I stimulates renal tubular reabsorption of phosphate and increases 1alpha-hydroxylase activity in response to hypophosphatemia.
NIH ExPorter
NIH ExPorter