Regulation of cell survival by Na+/H+ exchanger-1.
Na(+)/H(+) exchanger-1 (NHE1) is a ubiquitous plasma membrane Na(+)/H(+) exchanger typically associated with maintenance of intracellular volume and pH. In addition to the NHE1 role in electroneutral Na(+)/H(+) transport, in renal tubular epithelial cells in vitro the polybasic, juxtamembrane NHE1 cytosolic tail domain acts as a scaffold, by binding with ezrin/radixin/moesin (ERM) proteins and phosphatidylinositol 4,5-bisphosphate, which initiates formation of a signaling complex that culminates in Akt activation and opposition to initial apoptotic stress. With robust apoptotic stimuli renal tubular epithelial cell NHE1 is a caspase substrate, and proteolytic cleavage may permit progression to apoptotic cell death. In vivo, genetic or pharmacological NHE1 loss of function causes renal tubule epithelial cell apoptosis and renal dysfunction following streptozotocin-induced diabetes, ureteral obstruction, and adriamycin-induced podocyte toxicity. Taken together, substantial in vivo and in vitro data demonstrate that NHE1 regulates tubular epithelial cell survival. In contrast to connotations of NHE1 as an unimportant "housekeeping" protein, this review highlights that NHE1 activity is critical for countering tubular atrophy and chronic renal disease progression.
Schelling
Jeffrey R
JR
Rammelkamp Center for Education and Research, 2500 MetroHealth Drive, Cleveland, OH 44109-1998, USA. jeffrey.schelling@case.edu
Abu Jawdeh
Bassam G
BG
D000818:Animals; D017209:Apoptosis; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002470:Cell Survival; D004847:Epithelial Cells / Q000502:physiology*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000502:physiology*; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000502:physiology*
D027682:Cation Transport Proteins; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers