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

Irfana Soomro, Ying Sun, Zhai Li, Lonnette Diggs, Georgia Hatzivassiliou, Ajit G. Thomas, Rana Rais, Barbara Slusher, Stefan Somlo, Edward Y. Skolnik

Research output: Contribution to journalArticle

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-phe-nylacetamido-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.

Original languageEnglish (US)
Pages (from-to)1343-1353
Number of pages11
JournalNephrology Dialysis Transplantation
Volume33
Issue number8
DOIs
StatePublished - Jan 1 2018

Fingerprint

Glutaminase
Autosomal Dominant Polycystic Kidney
Glutamine
Cysts
Growth
Kidney
Mitogen-Activated Protein Kinase Kinases
Sulfides
Colforsin
Sirolimus
Metabolic Networks and Pathways
CB-839
Protein Isoforms
Collagen
Epithelium
Animal Models
Adenosine Triphosphate
Epithelial Cells
Cell Proliferation

Keywords

  • ADPKD
  • Glutaminase 1
  • Glutamine
  • Metabolism
  • Warburg effect for ESRD

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Soomro, I., Sun, Y., Li, Z., Diggs, L., Hatzivassiliou, G., Thomas, A. G., ... Skolnik, E. Y. (2018). Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease. Nephrology Dialysis Transplantation, 33(8), 1343-1353. https://doi.org/10.1093/ndt/gfx349

Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease. / Soomro, Irfana; Sun, Ying; Li, Zhai; Diggs, Lonnette; Hatzivassiliou, Georgia; Thomas, Ajit G.; Rais, Rana; Slusher, Barbara; Somlo, Stefan; Skolnik, Edward Y.

In: Nephrology Dialysis Transplantation, Vol. 33, No. 8, 01.01.2018, p. 1343-1353.

Research output: Contribution to journalArticle

Soomro, I, Sun, Y, Li, Z, Diggs, L, Hatzivassiliou, G, Thomas, AG, Rais, R, Slusher, B, Somlo, S & Skolnik, EY 2018, 'Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease', Nephrology Dialysis Transplantation, vol. 33, no. 8, pp. 1343-1353. https://doi.org/10.1093/ndt/gfx349
Soomro, Irfana ; Sun, Ying ; Li, Zhai ; Diggs, Lonnette ; Hatzivassiliou, Georgia ; Thomas, Ajit G. ; Rais, Rana ; Slusher, Barbara ; Somlo, Stefan ; Skolnik, Edward Y. / Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease. In: Nephrology Dialysis Transplantation. 2018 ; Vol. 33, No. 8. pp. 1343-1353.
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AU - Hatzivassiliou, Georgia

AU - Thomas, Ajit G.

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AB - 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-phe-nylacetamido-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.

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