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

30 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

ASJC Scopus subject areas

  • Nephrology

Fingerprint Dive into the research topics of 'Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms'. Together they form a unique fingerprint.

  • Cite this