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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 and Hirofumi Makino^*

^* Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan; and Northwestern University, The Feinberg School of Medicine, Department of Pathology, Chicago, Illinois

Address correspondence to: Dr. Jun Wada, Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1, Shikata-cho, Okayama 700-8558, Japan. Phone: +81-86-235-7235; Fax: +81-86-222-5214; junwada{at}md.okayama-u.ac.jp

Received for publication November 6, 2004. Accepted for publication August 9, 2005.

Galectins are -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 CD8⁺ T cells in nephrotoxic serum nephritis model. In this study, the effect of Gal-9 on G1-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-1 and the number of p27^Kip1- and p21^Cip1-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 p27^Kip1 and p21^Cip1 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-1 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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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673