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This research proposal has the long-term objective of improving our understanding of the mechanisms whereby hormones and ions control the renal synthesis of 1,25(OH)2D3. Using kidney proximal tubules prepared from vitamin D-replete rats, we propose to explore the role of cyclic AMP and cytosolic calcium as regulatory intracellular messengers of the mitochondrial 25-hydroxy-1-hydoxylase (10Hase) during enzyme stimulation by low calcium diet, dietary phosphorus deprivation, and parathyroid hormone. We plan to test the effects of manipulating cell cAMP on 10Hase by using hormones that stimulate adenylate cyclase, adenylate cyclase inhibitors and dibutryl cyclic AMP. We also plan to test the regulatory role of mitochondrial calcium influx and efflux by measuring 10Hase activity while altering cytosolic calcium with ionophores and inhibitors of plasma membrane and mitochondrial membrane calcium transport. Because 1,25(OH)2D3 plays an important role in regulating intestinal calcium absorption, bone mineralization and blood ionized calcium, dysregulation of the production of this steroid hormone can result in bone disease, soft tissue calcification, urolithiasis or renal impairment. Treatment of these conditions will be more rational if the fundamental disturbances are known in detail.
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