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Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting.

Publication ,  Journal Article
Shenolikar, S; Voltz, JW; Minkoff, CM; Wade, JB; Weinman, EJ
Published in: Proc Natl Acad Sci U S A
August 20, 2002

Na+/H+ exchanger regulatory factor (NHERF)-1 and NHERF-2, two structurally related protein adapters containing tandem PSD-95/Discs large/ZO-1 (PDZ) domains, were identified as essential factors for protein kinase A-mediated inhibition of the sodium-hydrogen exchanger, NHE3. NHERF-1 and NHERF-2 also bound other cellular targets including the sodium-phosphate cotransporter type IIa encoded by the NPT2 gene. Targeted disruption of the mouse NHERF-1 gene eliminated NHERF-1 expression in kidney and other tissues of the mutant mice without altering NHERF-2 levels in these tissues. NHERF-1 (+/-) and (-/-) male mice maintained normal blood electrolytes but showed increased urinary excretion of phosphate when compared with wild-type (+/+) animals. Although the overall levels of renal NHERF-1 targets, NHE3 and Npt2, were unchanged in the mutant mice, immunocytochemistry showed that the Npt2 protein was aberrantly localized at internal sites in the renal proximal tubule cells. The mislocalization of Npt2 paralleled a reduction in the transporter protein in renal brush-border membranes isolated from the mutant mice. In contrast, NHE3 was appropriately localized at the apical surface of proximal tubules in both wild-type and mutant mice. These data suggested that NHERF-1 played a unique role in the apical targeting and/or trafficking of Npt2 in the mammalian kidney, a function not shared by NHERF-2 or other renal PDZ proteins. Phosphate wasting seen in the NHERF-1(-/-) null mice provided a new experimental system for defining the role of PDZ adapters in the hormonal control of ion transport and renal disease.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

August 20, 2002

Volume

99

Issue

17

Start / End Page

11470 / 11475

Location

United States

Related Subject Headings

  • Symporters
  • Sodium-Phosphate Cotransporter Proteins, Type IIa
  • Sodium-Phosphate Cotransporter Proteins, Type III
  • Sodium-Phosphate Cotransporter Proteins, Type I
  • Sodium-Phosphate Cotransporter Proteins
  • Sodium-Hydrogen Exchangers
  • Sequence Deletion
  • Promoter Regions, Genetic
  • Polymerase Chain Reaction
  • Phosphoproteins
 

Citation

APA
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ICMJE
MLA
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Shenolikar, S., Voltz, J. W., Minkoff, C. M., Wade, J. B., & Weinman, E. J. (2002). Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proc Natl Acad Sci U S A, 99(17), 11470–11475. https://doi.org/10.1073/pnas.162232699
Shenolikar, S., J. W. Voltz, C. M. Minkoff, J. B. Wade, and E. J. Weinman. “Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting.Proc Natl Acad Sci U S A 99, no. 17 (August 20, 2002): 11470–75. https://doi.org/10.1073/pnas.162232699.
Shenolikar S, Voltz JW, Minkoff CM, Wade JB, Weinman EJ. Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11470–5.
Shenolikar, S., et al. “Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting.Proc Natl Acad Sci U S A, vol. 99, no. 17, Aug. 2002, pp. 11470–75. Pubmed, doi:10.1073/pnas.162232699.
Shenolikar S, Voltz JW, Minkoff CM, Wade JB, Weinman EJ. Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11470–11475.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

August 20, 2002

Volume

99

Issue

17

Start / End Page

11470 / 11475

Location

United States

Related Subject Headings

  • Symporters
  • Sodium-Phosphate Cotransporter Proteins, Type IIa
  • Sodium-Phosphate Cotransporter Proteins, Type III
  • Sodium-Phosphate Cotransporter Proteins, Type I
  • Sodium-Phosphate Cotransporter Proteins
  • Sodium-Hydrogen Exchangers
  • Sequence Deletion
  • Promoter Regions, Genetic
  • Polymerase Chain Reaction
  • Phosphoproteins