Format

Send to

Choose Destination
Nephrol Dial Transplant. 2018 Aug 1;33(8):1343-1353. doi: 10.1093/ndt/gfx349.

Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease.

Author information

1
Division of Nephrology, New York University Langone Medical Center, New York, NY, USA.
2
The Helen L. and Martin S. Kimmel Center for Biology and Medicine, New York University Langone Medical Center, New York, NY, USA.
3
Skirball Institute for Biomolecular Medicine, New York University Langone Medical Center, New York, NY, USA.
4
Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.
5
Cancer Immunology, Genentech, South San Francisco, CA, USA.
6
Department of Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
7
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
8
Department of Biochemistry, New York University Langone Medical Center, New York, NY, USA.
9
Department of Molecular Pharmacology and Molecular Pathogenesis, New York University Langone Medical Center, New York, NY, USA.

Abstract

Background:

Metabolism of glutamine by glutaminase 1 (GLS1) plays a key role in tumor cell proliferation via the generation of ATP and intermediates required for macromolecular synthesis. We hypothesized that glutamine metabolism also plays a role in proliferation of autosomal-dominant polycystic kidney disease (ADPKD) cells and that inhibiting GLS1 could slow cyst growth in animal models of ADPKD.

Methods:

Primary normal human kidney and ADPKD human cyst-lining epithelial cells were cultured in the presence or absence of two pharmacologic inhibitors of GLS1, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) and CB-839, and the effect on proliferation, cyst growth in collagen and activation of downstream signaling pathways were assessed. We then determined if inhibiting GLS1 in vivo with CB-839 in the Aqp2-Cre; Pkd1fl/fl and Pkhd1-Cre; Pkd1fl/fl mouse models of ADPKD slowed cyst growth.

Results:

We found that an isoform of GLS1 (GLS1-GAC) is upregulated in cyst-lining epithelia in human ADPKD kidneys and in mouse models of ADPKD. Both BPTES and CB-839 blocked forskolin-induced cyst formation in vitro. Inhibiting GLS1 in vivo with CB-839 led to variable outcomes in two mouse models of ADPKD. CB-839 slowed cyst growth in Aqp2-Cre; Pkd1fl/fl mice, but not in Pkhd1-Cre; Pkd1fl/fl mice. While CB-839 inhibited mammalian target of rapamycin (mTOR) and MEK activation in Aqp2-Cre; Pkd1fl/fl, it did not in Pkhd1-Cre; Pkd1fl/fl mice.

Conclusion:

These findings provide support that alteration in glutamine metabolism may play a role in cyst growth. However, testing in other models of PKD and identification of the compensatory metabolic changes that bypass GLS1 inhibition will be critical to validate GLS1 as a drug target either alone or when combined with inhibitors of other metabolic pathways.

PMID:
29420817
PMCID:
PMC6070111
DOI:
10.1093/ndt/gfx349

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center