Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy

Biochem Biophys Res Commun. 2003 Jun 13;305(4):1002-7. doi: 10.1016/s0006-291x(03)00885-4.


Transforming growth factor-beta (TGF-beta) has been implicated in the development of diabetic glomerulopathy. In order to evaluate a role of Smad3, one of the major signaling molecules downstream of TGF-beta, in the pathogenesis of diabetic glomerulopathy, Smad3-null mice were made diabetic with streptozotocin injection and analyzed 4 weeks after induction of diabetes. Electron microscopy revealed that the thickness of glomerular basement membrane (GBM) in wild-type diabetic mice was significantly higher than that in non-diabetic mice, whereas no appreciable GBM thickening was found in Smad3-null diabetic mice. Urinary albumin excretion was dramatically increased in wild-type diabetic mice, whereas Smad3-null diabetic mice did not show any overt albuminuria. Northern blotting revealed that mRNA levels of fibronectin and alpha 3 chain of type IV collagen (alpha 3Col4) in renal cortex of wild-type diabetic mice were approximately twice as much as those of non-diabetic mice, whereas their mRNA levels were not increased in Smad3-null diabetic mice. Real-time polymerase chain reaction (PCR) also confirmed diabetes-induced upregulation of fibronectin and alpha 3Col4 in glomeruli of wild-type mice. Glomerular expression of TGF-beta 1, as assessed by real-time PCR, was enhanced to a similar degree in wild-type and smad3-null diabetic mice, indicating that the observed differences between wild-type and Smad3-null mice are not attributable to difference in the expression of TGF-beta 1. These data clearly demonstrate a critical role of Smad3 in the early phase of diabetic glomerulopathy. This may be due at least partly to the present findings that diabetes-induced upregulation of fibronectin and alpha 3Col4 is dependent on Smad3 function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / etiology
  • Animals
  • Collagen Type IV / biosynthesis
  • Collagen Type IV / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Diabetes Mellitus, Experimental / etiology*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / etiology*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Fibronectins / biosynthesis
  • Fibronectins / genetics
  • Kidney Glomerulus* / ultrastructure
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Smad3 Protein
  • Trans-Activators / genetics
  • Trans-Activators / physiology*
  • Transcription, Genetic
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta1


  • Collagen Type IV
  • DNA-Binding Proteins
  • Fibronectins
  • Smad3 Protein
  • Smad3 protein, mouse
  • Tgfb1 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1