Each of the cell types of the nephron possesses segment-specific structural and biochemical specializations that both reflect and define its physiological properties. Nephron transport requires the asymmetric apportioning of ion transport proteins among the apical and basolateral plasma membrane domains of tubule epithelial cells. Polarized plasma membrane domains are a prerequisite for normal renal function, and their perturbation contributes to a variety of pathologies. To accommodate transport proteins, renal epithelial cells sculpt their plasma membranes into organized domains whose designs are exquisitely well suited to their physiological occupations. Furthermore, the organelles that populate renal epithelial cells participate in contacts and communication pathways through which they help to meet the metabolic, structural and biosynthetic demands imposed by renal transport. Elucidating the network of interactions that generate and maintain renal epithelial cell structure is central to understanding renal physiology. The past several years have seen the emergence of completely new understandings of the mechanisms through which the membranes of subcellular organelles communicate with one another and with the molecules that govern vesicular transport. A wide variety of membrane contact sites have been identified that not only tether subcellular structures to one another but also mediate inter-organelle communication and exchange. The inositol phospholipid compositions of organelle membranes and of sub-domains of the plasmalemma help to establish the identities of these membranes and define their interactions with the cellular sorting and trafficking machinery. While the roles of these contact sites and of the segregated distributions of inositol phospholipids has been established extensively in cultured cell systems, very little is known of their physiologic functions in epithelial cells that line renal tubules in situ. We hypothesize that the unique architecture of renal epithelial cells is predicated upon contact-mediated and inositol phospholipid-mediated communication among subcellular compartments. The studies outlined in the present proposal will explore the mechanisms through which renal tubule epithelial cell plasma membranes acquire and modulate some of their characteristic adaptations. The hypothesis that motivates these studies is that renal epithelial cell structure and function are predicated upon networks of protein-protein interactions and signaling pathways that collaborate with one another to communicate and respond to environmental cues. To explore this hypothesis and its implications in depth we will: 1) Define the nature, localization and ontogeny of membrane contact sites in renal epithelial cells; 2) Define the biochemical compositions of contact sites in the kidney and the roles of contact sites in renal development and function; and 3) Define the distributions of inositol phospholipids in renal epithelial cells in vivo and determine their roles in determining these cells' polarized structures. Thus, the studies outlined in this proposal will provide new cellular and molecular insights into the processes through which renal epithelial cells acquire the structures that their function demands.
Kidney cells carry out ion transport that is responsible for determining the body's salt and water composition. To fulfil this responsibility, kidney cells must organize their surface domains into structures that accommodate the different protein compositions that determine their functional characteristics. Developing insight into the mechanisms that generate and maintain this structural organization is a critical prerequisite to understanding the physiology of the kidney.
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