Renal cysts are central pathologic features of a number of congenital human disease states. Although thereby responsible for significant morbidity and mortality in both children and adults, the basic causes of renal cystic maldevelopment remain unknown. The current proposal is designed to study the pathogenesis of tubular cyst formation and progressive enlargement in autosomal recessive polycystic kidney disease of CPK mice. The study of proximal tubular cystic maldevelopment in CPK kidneys, both in vivo and in previously described organ culture model systems of murine metanephric development in vitro, will afford the opportunity to study the factors operative in naturally occurring cystogenesis under highly controlled experimental conditions. An experimental hypothesis has been constructed to direct the studies of the current investigation. This hypothesis proposes that: a) proximal tubular cyst formation in CPK mice is associated with increases in renal Na-K ATPase activity; b) proximal tubular epithelial hyperplasia and increased transtubular transport of organic anions occur in relation to such increases in enzyme activity; and c) fluid secretion obligated by the net intratubular accumulation of osmotically active organic anions in hyperplastic nephron segments leads to consequent tubular dilatation and cyst formation. In testing each of the premises of the proposed hypothesis, the basic technique of serum-free metanephric organ culture will be utilized in concert with methods developed for: kinetic microassay of renal Na-K ATPase activity in isolated nephron segments; nephron microdissection; and autoradiography and measurement of radioisotopic uptake of (3H) thymidine and (3H) PAH in metanephric microslices and isolated brush border and basolateral membrane vesicles. Such studies will identify potential renal cyst-promoting roles for Na-K ATPase activity, tubular epithelial cell hyperplasia, and organic anion transport in the CPK mouse and characterize their interactions in mediating in vivo and in vitro proximal tubular cyst formation. The characterization of proximal tubular cyst formation in this experimental model may provide further insight into the complex pathogenesis of renal cyst formation and progressive enlargement in human cystic disease states.
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