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Na+–H+ exchanger-1 (NHE1) regulation in kidney proximal tubule

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Abstract

The ubiquitously expressed plasma membrane Na+–H+ exchanger NHE1 is a 12 transmembrane-spanning protein that directs important cell functions such as homeostatic intracellular volume and pH control. The 315 amino acid cytosolic tail of NHE1 binds plasma membrane phospholipids and multiple proteins that regulate additional, ion-translocation independent functions. This review focuses on NHE1 structure/function relationships, as well as the role of NHE1 in kidney proximal tubule functions, including pH regulation, vectorial Na+ transport, cell volume control and cell survival. The implications of these functions are particularly critical in the setting of progressive, albuminuric kidney diseases, where the accumulation of reabsorbed fatty acids leads to disruption of NHE1-membrane phospholipid interactions and tubular atrophy, which is a poor prognostic factor for progression to end stage renal disease. This review amplifies the vital role of the proximal tubule NHE1 Na+–H+ exchanger as a kidney cell survival factor.

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Notes

  1. NHE3 is the transporter responsible for the activity originally detected in the apical membranes preparations from rat proximal tubules.

  2. The K m for intracellular H+ in pH units is sometimes referred to as pK i. Note that ‘pK i’ is not defined as the protonation state of titratable groups in the protein.

  3. Another determinant, Gly346 at the extracellular end of TM9, is hypothesized to be in three-dimensional proximity to the clustered determinants in TM4 [24].

Abbreviations

AE2:

Anion exchange protein 2

AKI:

Acute kidney injury

CHP1:

Calcineurin-homologous protein 1

CKD:

Chronic kidney disease

ERM:

Ezrin/radixin/moesin

ESRD:

End stage renal disease

JAK2:

Janus kinase 2

LC-CoA:

Long chain fatty acyl-CoA

MDCK:

Madin-Darby canine kidney cell line

NaPi-IIa:

Na+-phosphate co-transporter

NBC:

Na+/HCO3 − co-transporter

NCX1:

Na+–Ca2+ exchanger 1

NHE:

Na+–H+ exchanger

NIK:

Nck (non-catalytic region of tyrosine kinase adaptor protein 1)-interacting kinase

NKCC1:

Na+/K+/Cl− co-transporter 1

pHi :

Intracellular pH

PI(4,5)P2:

Phosphatidylinositol 4,5-bisphosphate

ROCK1:

Rho-associated, coiled-coil-containing protein kinase 1

RVI:

Regulatory volume increase

SGK1:

Serum and glucocorticoid-regulated kinase 1

SGLT:

Sodium-glucose co-transporter

TM:

Transmembrane-spanning domain

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  1. Department of Physiology and Biophysics, University at Buffalo: The State University of New York, Buffalo, NY, 14214, USA

    Mark D. Parker & Evan J. Myers

  2. Department of Ophthalmology, University at Buffalo: The State University of New York, Buffalo, NY, 14214, USA

    Mark D. Parker

  3. Department of Medicine, Case Western Reserve University, Cleveland, OH, 44109, USA

    Jeffrey R. Schelling

  4. MetroHealth Medical Center, 2500 MetroHealth Drive, Rammelkamp Building, R425, Cleveland, OH, 44109, USA

    Jeffrey R. Schelling

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Parker, M.D., Myers, E.J. & Schelling, J.R. Na+–H+ exchanger-1 (NHE1) regulation in kidney proximal tubule. Cell. Mol. Life Sci. 72, 2061–2074 (2015). https://doi.org/10.1007/s00018-015-1848-8

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