Format

Send to

Choose Destination
See comment in PubMed Commons below
J Am Soc Nephrol. 2017 May;28(5):1399-1407. doi: 10.1681/ASN.2016080913. Epub 2016 Nov 28.

Kidney Tubular Ablation of Ocrl/Inpp5b Phenocopies Lowe Syndrome Tubulopathy.

Inoue K1, Balkin DM2,3,4, Liu L2,3,4,5, Nandez R2,3,4, Wu Y2,3,4,5, Tian X1, Wang T6, Nussbaum R7,8,3, De Camilli P9,3,4,5, Ishibe S10,6.

Author information

1
Departments of Internal Medicine.
2
Cell Biology.
3
Howard Hughes Medical Institute, and.
4
Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, Connecticut.
5
Neuroscience, and.
6
Cellular and Molecular Physiology.
7
Department of Medicine and.
8
Institute of Human Genetics, University of California, San Francisco, California; and.
9
Cell Biology, pietro.decamilli@yale.edu shuta.ishibe@yale.edu.
10
Departments of Internal Medicine, pietro.decamilli@yale.edu shuta.ishibe@yale.edu.

Abstract

Lowe syndrome and Dent disease are two conditions that result from mutations of the inositol 5-phosphatase oculocerebrorenal syndrome of Lowe (OCRL) and share the feature of impaired kidney proximal tubule function. Genetic ablation of Ocrl in mice failed to recapitulate the human phenotypes, possibly because of the redundant functions of OCRL and its paralog type 2 inositol polyphosphate-5-phosphatase (INPP5B). Germline knockout of both paralogs in mice results in early embryonic lethality. We report that kidney tubule-specific inactivation of Inpp5b on a global Ocrl-knockout mouse background resulted in low molecular weight proteinuria, phosphaturia, and acidemia. At the cellular level, we observed a striking impairment of clathrin-dependent and -independent endocytosis in proximal tubules, phenocopying what has been reported for Dent disease caused by mutations in the gene encoding endosomal proton-chloride exchange transporter 5. These results suggest that the functions of OCRL/INPP5B and proton-chloride exchange transporter 5 converge on shared mechanisms, the impairment of which has a dramatic effect on proximal tubule endocytosis.

KEYWORDS:

INPP5B; Lowe syndrome; OCRL; endocytosis; proximal tubulopathy

PMID:
27895154
PMCID:
PMC5407733
[Available on 2018-05-01]
DOI:
10.1681/ASN.2016080913
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Support Center