We propose three major areas of investigation: 1) Glomerular and mesangial cell contractility will be studied using a computer-based image analysis microscopic system. We will assess the contractile effects of thromboxane A2, leukotriene C4 and D4, and platelet activating factor on isolated rat glomeruli and rat glomerular mesangial cells in culture. The glomerular contractile actions of these compounds will be blocked with specific antagonists to thromboxane receptors and leukotriene receptors. The relaxant effect of PGE2 or PGI2 will be studied and the role of intracellular cyclic AMP as the mediator of mesangial relaxation will be evaluated. The importance of calcium entry or translocation of intracellular calcium as a mediator of mesangial contraction in response to the aforementioned contractile agents will also be studied; 2) Studies of glomerular immune injury will use several models of nephrotoxic serum nephritis induced by antiglomerular basement membrane antibodies. Glomerular synthesis of leukotriene B4, C4 and D4 will be measured in normal and immune-injured glomeruli. The actions of LTC4 and LTD4 on glomerular function in vivo will be evaluated, after intrarenal infusion in the rat, with measurements of glomerular filtration rate, renal blood flow and urinary protein excretion. The therapeutic efficacy of lipoxygenase inhibitors in nephrotoxic serum nephritis will be evaluated as will the value of a leukotriene D4 receptor antagonist; 3) Renal medullary prostaglandin synthesis will be measured in salt-sensitive, hypertensive Dahl rats. Using cell culture techniques, we will determine whether reduced PGE2 synthesis is in renal medullary interstitial cells or renal papillary collecting tubular cells. Renal medullary interstitial cell synthesis of anti-hypertensive polar renomedullary lipid (platelet activating factor) will be measured and compared between hypertensive and normotensive rats. Transepithelial salt transport will be assessed in renal papillary collecting tubular cell monolayers and we will determine whether this is the site of enhanced sodium reabsorption in hypertensive salt-sensitive rats. The effects of prostaglandins and platelet activating factor on renal papillary collecting tubular cell transport will be measured.
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