Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms

Masako Baba, Jun Wada, Jun Eguchi, Izumi Hashimoto, Tatsuo Okada, Akihiro Yasuhara, Kenichi Shikata, Yashpal S. Kanwar, Hirofumi Makino

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Galectins are β-galactoside-binding lectins that are involved in various biologic processes, such as apoptosis, cell proliferation, and cell-cycle regulation. Galectin-9 (Gal-9) was identified previously and demonstrated to have apoptotic potential to thymocytes in mice and activated CDS+ T cells in nephrotoxic serum nephritis model. In this study, the effect of Gal-9 on Gl-phase cell-cycle arrest, one of the hallmark pathologic changes in early diabetic nephropathy, was investigated. Eight-week-old male db/db mice received injections of recombinant Gal-9 or vehicle for 8 wk. The injection of Gal-9 into db/db mice significantly inhibited glomerular hypertrophy and mesangial matrix expansion and reduced urinary albumin excretion. Gal-9 reduced glomerular expression of TGF-β1 and the number of p27Kip1- and p21Cip1-positive cells in glomeruli. Double staining with nephrin and type IV collagen revealed that podocytes were mainly positive for p27 Kip1. For further confirming the cell-cycle regulation by Gal-9, conditionally immortalized mouse podocyte cells were cultured under 5.5 and 25 mM D-glucose supplemented with Gal-9. Cell-cycle distribution analyses revealed that Gal-9 maintained further progression of cell cycle from the G1 phase. Gal-9 reversed the high-glucose-mediated upregulation of p27Kip1 and p21Cip1 and inhibited cell-cycle-dependent hypertrophy, i.e., reduced [3H]proline incorporation. The data suggest that Gal-9 plays a central role in inducing their successful progression from G1 to G2 phase by suppressing glomerular expression of TGF-βl and inhibition of cyclin-dependent kinase inhibitors. Gal-9 may give an impetus to develop new therapeutic tools targeted toward diabetic nephropathy.

Original languageEnglish
Pages (from-to)3222-3234
Number of pages13
JournalJournal of the American Society of Nephrology
Volume16
Issue number11
DOIs
Publication statusPublished - 2005

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Galectins
Hypertrophy
Cell Cycle
Podocytes
Diabetic Nephropathies
Glucose
Galactosides
Injections
Collagen Type IV
Cyclin-Dependent Kinases
Nephritis
G2 Phase
G1 Phase
Thymocytes
Cell Cycle Checkpoints
Lectins
Proline
Albumins
Cultured Cells

ASJC Scopus subject areas

  • Nephrology

Cite this

Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms. / Baba, Masako; Wada, Jun; Eguchi, Jun; Hashimoto, Izumi; Okada, Tatsuo; Yasuhara, Akihiro; Shikata, Kenichi; Kanwar, Yashpal S.; Makino, Hirofumi.

In: Journal of the American Society of Nephrology, Vol. 16, No. 11, 2005, p. 3222-3234.

Research output: Contribution to journalArticle

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AU - Hashimoto, Izumi

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AU - Shikata, Kenichi

AU - Kanwar, Yashpal S.

AU - Makino, Hirofumi

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AB - Galectins are β-galactoside-binding lectins that are involved in various biologic processes, such as apoptosis, cell proliferation, and cell-cycle regulation. Galectin-9 (Gal-9) was identified previously and demonstrated to have apoptotic potential to thymocytes in mice and activated CDS+ T cells in nephrotoxic serum nephritis model. In this study, the effect of Gal-9 on Gl-phase cell-cycle arrest, one of the hallmark pathologic changes in early diabetic nephropathy, was investigated. Eight-week-old male db/db mice received injections of recombinant Gal-9 or vehicle for 8 wk. The injection of Gal-9 into db/db mice significantly inhibited glomerular hypertrophy and mesangial matrix expansion and reduced urinary albumin excretion. Gal-9 reduced glomerular expression of TGF-β1 and the number of p27Kip1- and p21Cip1-positive cells in glomeruli. Double staining with nephrin and type IV collagen revealed that podocytes were mainly positive for p27 Kip1. For further confirming the cell-cycle regulation by Gal-9, conditionally immortalized mouse podocyte cells were cultured under 5.5 and 25 mM D-glucose supplemented with Gal-9. Cell-cycle distribution analyses revealed that Gal-9 maintained further progression of cell cycle from the G1 phase. Gal-9 reversed the high-glucose-mediated upregulation of p27Kip1 and p21Cip1 and inhibited cell-cycle-dependent hypertrophy, i.e., reduced [3H]proline incorporation. The data suggest that Gal-9 plays a central role in inducing their successful progression from G1 to G2 phase by suppressing glomerular expression of TGF-βl and inhibition of cyclin-dependent kinase inhibitors. Gal-9 may give an impetus to develop new therapeutic tools targeted toward diabetic nephropathy.

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