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

J Am Soc Nephrol. 2005 Nov;16(11):3222-34. doi: 10.1681/ASN.2004110915. Epub 2005 Sep 21.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Culture Techniques
  • Cell Cycle
  • DNA Primers
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Disease Models, Animal
  • Galectins / pharmacology*
  • Galectins / physiology
  • Glucose / pharmacology
  • Hypertrophy
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / pathology*
  • Kidney Glomerulus / physiopathology*
  • Male
  • Mice
  • Mice, Mutant Strains
  • Podocytes / drug effects
  • Podocytes / physiology*
  • Polymerase Chain Reaction
  • Recombinant Proteins / pharmacology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta1


  • DNA Primers
  • Galectins
  • Recombinant Proteins
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • galectin 9, mouse
  • Glucose