The processes that lead to the development and interaction of the specific absorptive and secretory functions of different nephron segments have not been evaluated in details. Recent studies have suggested that transition from metanephrogenic mesenchyme to functional epithelium is accompanied by reorganization and repatterning of plasma membrane ion channel expression and conductance. Studies by our group, as well as others have shown that Na+/K+-ATPase is localized to the apical membrane during early tubulogenesis and repolarized to the basolateral membrane later during development. Preliminary studies have demonstrated that alterations in the integrity of the fetal environment such as fetal hyperglycemia may have a profound effect on the normal development of Na+/K+-ATPase polarization. The present proposal is designed to investigate in normal and pathological states (i.e., fetal hyperglycemia secondary to maternal diabetes) the mechanisms regulating the development of vectorial transport function in the kidney using Na+/K+-ATPase as a marker of tubular epithelial polarity. To achieve this aim we are proposing to test three specific hypotheses: (1) fetal hyperglycemia (as observed during maternal diabetes mellitus) leads to abnormalities of basolateral polarization of Na+/K+-ATPase and rearrangements of cytoskeleton proteins, namely ankyrin and spectrin; (2) phosphorylation of Na+/K+-ATPase and associated cytoskeleton proteins contributes to the development of Na+/K+-ATPase polarization and that fetal hyperglycemia alters these mechanisms; (3) abnormalities in epithelial Na+/K+-ATPase polarity originating during kidney embryogenesis become imprinted and lead to permanent alterations in tubular cellular organization postnatally.
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