A major objective of the proposed is to further clarify the pathophysiology of chronic renal disease, urinary tract obstruction, acute renal failure, and uremia by the use of physiologic, metabolic, biochemical and cell biology techniques. Studies will be performed in animal with experimentally induced renal disease or electrolyte disturbances and experiments will be conducted in the animals in vivo (clearances, micropuncture, response to hormones, metabolism of hormones, production of prostaglandins, etc.) or in tissues or segments of tissues studied in vitro (isolated perfused nephron segments, brush border or basolateral membranes from renal cortex). Tissue cultures of different types of renal cells will also be utilized in some of the studies proposed. The different projects will examined: the modulation of epithelial transport by factors (such as interleukin I) released by immune cells (Project I); the role of membrane phospholipids and specific lipases in renal injury (Project 2); the mechanisms underlying the adaptation in tubule transport functions after reduction of renal mass, acid-base manipulation or hormonal exposure (Project 3); the mechanisms responsible for hemodynamic changes and decrease in GFR and subsequent loss of functional nephrons that occurs with obstructive uropathy (Project 4); the role of H+ ATPase in acidification defects that occur with renal disease and the cellular mechanisms underlying these defects. Other projects deal with different aspects of the mechanisms that control parathyroid hormone secretion in health and renal failure (Projects 6 and 8). Project 6 will examine the biogenesis of the hyperparathyroidism of renal failure and Project 8 will investigate the role of vitamin D in the pathogenesis of secondary hyperparathyroidism. Other projects will examine the physiological role of the peripheral metabolism of PTH (Project 7) and the mechanisms underlying the cellular effect of PTH at the level of the kidney (Project 9), including studies of cytosolic calcium, the phosphatidylinositol pathway, and its interaction with the cyclic AMP system. All of these project (6 through 9) represent logical extensions of work currently in progress in these different laboratories. Project 10 proposes to characterize the transport of glucose and its regulation in proximal tubular cells of normal animals and animals with reduced renal mass.
