Despite enormous advances in the diagnosis and management of patients with end-stage renal diseases, little progress has been made in understanding the pathogenetic factors which are responsible for the loss of functional kidney tissue in hundreds of thousands of patients each year in this country alone. Recently, observations have been made in both patients and animals suggesting that glomerular capillary hyperperfusion may be a common pathogenetic event in the generation of this inexorably progressive lesion. Further, evidence will be presented in detail in this application which suggest that the prostaglandins may be the mediator of these glomerular hemodynamic changes.
The aim of this study is to explore and define the physiology and pathophysiology of the arachidonic acid metabolites produced by the isolated glomerulus and renal afferent arteriole in normal animals and animals with progressive renal diseases and on varying protein intake. Preliminary studies have been performed to establish reproducible methods of preparing isolated glomeruli and microvessels. High pressure liquid chromatographic methods have been designed to measure prostaglandins in biological samples in addition to the radioimmuno- and membrane receptor assays already available in this laboratory. Several groups of protocols have been designed to evaluate arachidonic acid metabolism and prostaglandin metabolism by tissue from both normal animals and animals with at least three different forms of chronic renal disease in various stages of progression of renal impairment. Other studies will evaluate the effect on arachidonic acid metabolism of several vasoactive hormones which may influence glomerular function in renal diseases. Specific studies will be performed to attempt to alter the progression of chronic renal disease by manipulating both the production and action of certain key prostanoids. The final group of studies will examine the biology of prostaglandin receptors in renal microvascular tissue. This study is part of a continued interest that this laboratory has had in the physiology and pathophysiology of vasoactive hormones and the kidney and compliments the general interest and research goals of the other members of the Nephrology division at UCLA. The results of these studies will add to the growing body of information about the pathogenetic mechanisms which occur in chronic progressive renal disease. They will give a better understanding of the determinants of the hemodynamic basis for progressive nephron loss and may contribute to the eventual discovery of the cure for these seemingly uncontrollable and untreatable diseases.
