The role of NHERF-1 in the regulation of renal proximal tubule sodium-hydrogen exchanger 3 and sodium-dependent phosphate cotransporter 2a

Abstract

Adaptor proteins containing PDZ interactive domains have been recently identified to regulate the trafficking and activity of ion transporters and channels in epithelial tissue. In the renal proximal tubule, three PDZ adaptor proteins, namely NHERF-1, NHERF-2 and PDZK1, are expressed in the apical membrane, heterodimerize with one another, and, at least in vitro, are capable of binding to NHE3 and Npt2a, two major regulated renal proximal tubule apical membrane transporters. Studies using NHERF-1 null mice have begun to provide insights into the organization of these adaptor proteins and their specific interactions with NHE3 and Npt2a. Experiments using brush border membranes and cultured renal proximal tubule cells indicate a specific requirement for NHERF-1 for cAMP-mediated phosphorylation and inhibition of NHE3. NHERF-1 null mice demonstrate increased urinary excretion of phosphate associated with mistargeting of Npt2a to the apical membrane of renal proximal tubule cells. NHERF-1 null animals challenged with a low phosphate diet and proximal tubule cells from these animals cultured in a low phosphate media fail to adapt as well as wild-type mice. These studies indicate a unique requirement for NHERF-1 in cAMP regulation of NHE3 and in the trafficking of Npt2a.

Figure 1. The distribution of NHERF-1 and NHERF-2 in the renal proximal tubule of wild-type mice

A, representative confocal images of proximal convoluted tubules of the mouse kidney using antibodies specific for NHERF-1 (a) and NHERF-2 (b). c is the merged images showing the localization of NHERF-1 in the microvillar membranes and NHERF-2 predominantly in a region just below the microvilli. B, electron microscopical images of wild-type renal proximal tubules using immunogold showing the localization of NHERF-1 in the microvillus (a) and NHERF-2 in vesicle-rich region at the base of the microvilli (b). (Figures adapted from Wade et al. 2003.)

Figure 1. The distribution of NHERF-1 and NHERF-2 in the renal proximal tubule of wild-type mice

A, representative confocal images of proximal convoluted tubules of the mouse kidney using antibodies specific for NHERF-1 (a) and NHERF-2 (b). c is the merged images showing the localization of NHERF-1 in the microvillar membranes and NHERF-2 predominantly in a region just below the microvilli. B, electron microscopical images of wild-type renal proximal tubules using immunogold showing the localization of NHERF-1 in the microvillus (a) and NHERF-2 in vesicle-rich region at the base of the microvilli (b). (Figures adapted from Wade et al. 2003.)