Physiological Functions and Regulation of the Na⁺/H⁺ Exchanger [NHE1] in Renal Tubule Epithelial Cells

Abstract

The sodium-hydrogen exchanger isoform-1 [NHE1] is a ubiquitously expressed plasma membrane protein that plays a central role in intracellular pH and cell volume homeostasis by catalyzing an electroneutral exchange of extracellular sodium and intracellular hydrogen. Outside of this important physiological function, the NHE1 cytosolic tail domain acts as a molecular scaffold regulating cell survival and actin cytoskeleton organization through NHE1-dependent signaling proteins. NHE1 plays main roles in response to physiological stress conditions which in addition to cell shrinkage and acidification, include hypoxia and mechanical stimuli, such as cell stretch. NHE1-mediated modulation of programmed cell death results from the exchanger-mediated changes in pHi, cell volume, and/or [Na⁺]_I; and, it has recently become known that regulation of cellular signaling pathways are involved as well. This review focuses on NHE1 functions and regulations. We describe evidence showing how these structural actions integrate with ion translocation in regulating renal tubule epithelial cell survival.

Enhanced Reactive Oxygen Species Production, Acidic Cytosolic pH and Upregulated Na+/H+ Exchanger (NHE) in Dicer Deficient CD4+ T Cells

“…Briefly, in 10 µl reactions, 10 ng cDNA, KAPA SYBR ® FAST q-PCR kit Master Mix (2x) Bio-Rad iCycler TM (Peqlab, Erlangen, Germany) and 250 nM primers were used for q-RT-PCR reactions. q-RT-PCR run and data analysis was performed as described previously [43] for Nhe1 and Gapdh [37] using universal cycling conditions (95° C for 10 minutes, 95° C for 15 seconds and 60° C for 1 minute for 40 cycles followed by melting curve analysis) [43]. …”

Role of the sodium‐hydrogen exchanger in mediating the renal effects of drugs commonly used in the treatment of type 2 diabetes

“…The exchange of sodium for hydrogen ions across cell membranes is finely regulated by a family of antiporters that consist of at least 9 related isoforms . The sodium‐hydrogen exchanger isoform 1 (NHE1) is present in all cells, where it plays an important physiological role in maintaining cell volume and acidity within narrow limits . By contrast, the sodium‐hydrogen exchanger isoform 3 (NHE3) is limited to the apical surface of renal and gastrointestinal epithelial cells, where it mediates sodium reabsorption .…”

“…Both glucose and insulin induce the expression of NHE1 and NHE3 in the glomerular mesangium, tubular epithelium and vascular endothelium . Upregulation of NHE1 mediates the proliferation of mesangial cells, compromises the survival of renal tubular epithelial cells and promotes vascular abnormalities in diabetic kidneys . Increased NHE3 activity may contribute importantly to glomerular hyperfiltration, sodium retention and tubular cellular proliferation .…”

“…11 The sodium-hydrogen exchanger isoform 1 (NHE1) is present in all cells, where it plays an important physiological role in maintaining cell volume and acidity within narrow limits. 12 By contrast, the sodium-hydrogen exchanger isoform 3 (NHE3) is limited to the apical surface of renal and gastrointestinal epithelial cells, where it mediates sodium reabsorption. 13 The action of NHE3 accounts for a majority of the sodium reuptake that follows glomerular filtration.…”

“…[16][17][18][19] Upregulation of NHE1 mediates the proliferation of mesangial cells, compromises the survival of renal tubular epithelial cells and promotes vascular abnormalities in diabetic kidneys. 12,[20][21][22] Increased NHE3 activity may contribute importantly to glomerular hyperfiltration, sodium retention and tubular cellular proliferation. 18,23,24 Collectively, these changes are the hallmarks of diabetic nephropathy.…”