Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms.
Galectins are beta-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-beta1 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 [(3)H]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-beta1 and inhibition of cyclin-dependent kinase inhibitors. Gal-9 may give an impetus to develop new therapeutic tools targeted toward diabetic nephropathy.
Baba
Masako
M
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1, Shikata-cho, Okayama 700-8558, Japan.
Wada
Jun
J
Eguchi
Jun
J
Hashimoto
Izumi
I
Okada
Tatsuo
T
Yasuhara
Akihiro
A
Shikata
Kenichi
K
Kanwar
Yashpal S
YS
Makino
Hirofumi
H
D000818:Animals; D018929:Cell Culture Techniques; D002453:Cell Cycle; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004195:Disease Models, Animal; D037161:Galectins / Q000494:pharmacology* / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D006984:Hypertrophy; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D050199:Podocytes / Q000187:drug effects / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D017931:DNA Primers; D037161:Galectins; D011994:Recombinant Proteins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C508186:galectin 9, mouse; D005947:Glucose