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

¹Physiologisches Institut, University of Würzburg, 97070 Würzburg; ³Physiologisches Institut, Universität Duisburg-Essen, 45122 Essen, Germany; and ²Department of Molecular Genetics, Biochemistry, and Microbiology, The University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Submitted 20 February 2004 ; accepted in final form 22 April 2004

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 [¹⁴C]cytochrome c by 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.

urinary protein excretion; pH homeostasis

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