RED CELL CYTOSKELETON PROTEIN 4.1R IN KIDNEY FUNCTION

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Protein 4.1R is a red cell cytoskeletal protein which plays a key role in maintaining erythrocyte shape and deformability by bridging the spectrin-actin cytoskeleton to specific transmembrane proteins. The identification of 4.1R in various organelles of nucleated cells along with the recent characterization of three novel genes sharing very high homology with 4.1R have escalated the interest in studying the role of members of the protein 4.1 family in non erythroid cells. Over the past years, it has become clear that the cytoskeleton does not only provide support for the plasma membrane or segregate membrane proteins in specialized domains, but that it can also regulate the functions of such membrane proteins including various transporters. In kidney epithelia, functions of selected solute transporters and selective permeability of tight junctions depend on the integrity of the actin cytoskeleton. In situ hybridization of probes specific for each of the four 4.1 genes suggest that members of the protein 4.1 family may adopt specific distribution within selected tissues including brain and kidney. In the kidney, 4.1R seems to accumulate predominantly in the proximal tubule of the nephron, a region where most of renal reabsorption and/or secretion of water and solutes occur. Our working hypothesis is that 4.1R may regulate such functions of the proximal tubule by interacting with membrane transporters of the nephron epithelium. To investigate this possibility, we propose to 1) identify the renal isoforms of 4.1R and its homologs and characterize their distribution pattern within the kidney, 2) identify binding partners for 4.1R in the kidney, focusing in particular on membrane transporters and 3) compare renal function in wild type and 4.1R null mice in order to decipher the mechanisms by which 4.1R may regulate reabsorption and/or secretion by selected transporters and investigate whether the organization of tight junctions is compromised in 4.1R knock out mice. We anticipate that a detailed understanding of the functions of members of the protein 4.1 family in the epithelium of the nephron will shed light on kidney pathologies related to defects in cytoskeletal proteins.