NHE3 Na+/H+ exchanger supports proximal tubular protein reabsorption in vivo

Proximal tubular receptor-mediated endocytosis (RME) of filtered proteins prevents proteinuria. Pharmacological and genetic studies in cultured opossum kidney cells have shown that the apical Na(+)/H(+) exchanger isoform 3 (NHE3) supports RME by interference with endosomal pH homeostasis and endocyt...

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Published in:American journal of physiology. Renal physiology 2004-09, Vol.287 (3), p.F469-F473
Main Authors: Gekle, Michael, Völker, Katharina, Mildenberger, Sigrid, Freudinger, Ruth, Shull, Gary E, Wiemann, Martin
Format: Article
Language:English
Subjects:
Absorption - physiology
Animals
Homeostasis - physiology
Hydrogen-Ion Concentration
Kidney Tubules, Proximal - metabolism
Male
Mice
Mice, Knockout
Proteins - metabolism
Proteinuria - metabolism
Rats
Rats, Wistar
Sodium-Hydrogen Exchanger 3
Sodium-Hydrogen Exchangers - genetics
Sodium-Hydrogen Exchangers - metabolism
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Summary:Proximal tubular receptor-mediated endocytosis (RME) of filtered proteins prevents proteinuria. Pharmacological and genetic studies in cultured opossum kidney cells have shown that the apical Na(+)/H(+) exchanger isoform 3 (NHE3) supports RME by interference with endosomal pH homeostasis and endocytic fusion events. However, it is not known whether NHE3 also supports proximal tubular RME in vivo. We analyzed proximal tubular protein reabsorption by microinfusion experiments in rats and investigated renal protein excretion in NHE3 knockout (Nhe3 -/-) mice. Inhibition of NHE3 by EIPA or S-3226 reduced the fractional reabsorption of [(14)C]cytochrome c by approximately 50% during early proximal microinfusion. During early distal microinfusion, no protein reabsorption could be detected. Urinary protein excretion of Nhe3 -/- or heterozygous mutant mice was significantly higher compared with wild-type mice. SDS-PAGE analysis of urinary proteins revealed that Nhe3 -/- animals excreted proteins the size of albumin or smaller. Thus a reduction in NHE3 activity or abundance causes tubular proteinuria. These data show that NHE3 supports proximal tubular RME of filtered proteins in vivo.
ISSN:1931-857X
1522-1466
DOI:10.1152/ajprenal.00059.2004