Soluble betaglycan reduces renal damage progression in db/db mice

Am J Physiol Renal Physiol. 2007 Jan;292(1):F321-9. doi: 10.1152/ajprenal.00264.2006. Epub 2006 Sep 5.

Abstract

Transforming growth factor-beta (TGF-beta) is a key mediator in the pathogenesis of renal diseases. Betaglycan, also known as the type III TGF-beta receptor, regulates TGF-beta action by modulating its access to the type I and II receptors. Betaglycan potentiates TGF-beta; however, soluble betaglycan, which is produced by the shedding of the membrane-bound receptor, is a potent antagonist of TGF-beta. In the present work, we have used a recombinant form of soluble betaglycan (SBG) to prevent renal damage in genetically obese and diabetic db/db mice. Eight-wk-old db/db or nondiabetic (db/m) mice were injected intraperitoneally with 50 mug of SBG or vehicle alone three times a wk for 8 wk. The db/db mice that received vehicle presented albuminuria and increased serum creatinine, as well as glomerular mesangial matrix expansion. The db/db mice treated with SBG exhibited a reduction in serum creatinine, albuminuria, and structural renal damage. These effects were associated with lower kidney levels of mRNAs encoding TGF-beta1, TGF-beta2, TGF-beta3, collagen IV, collagen I, fibronectin, and serum glucocorticoid kinase as well as a reduction in the immunostaining of collagen IV and fibronectin. Our data indicate that SBG is a renoprotective agent that neutralized TGF-beta actions in this model of nephropathy. Because SBG has a high affinity for all TGF-beta isoforms, in particular TGF-beta2, it is found naturally in serum and tissues and its shedding may be regulated. We believe that SBG shall prove convenient for long-term treatment of kidney diseases and other pathologies in which TGF-beta plays a pathophysiological role.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / urine
  • Animals
  • Collagen / biosynthesis
  • Creatinine / blood
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / genetics
  • Disease Progression
  • Down-Regulation / drug effects
  • Fibronectins / metabolism
  • Glomerular Mesangium / pathology
  • Immunohistochemistry
  • Kidney Diseases / chemically induced*
  • Kidney Diseases / genetics
  • Kidney Diseases / pathology*
  • Kidney Glomerulus / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Polysaccharides / therapeutic use*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tissue Distribution
  • Transforming Growth Factor beta / antagonists & inhibitors

Substances

  • Fibronectins
  • Polysaccharides
  • RNA, Messenger
  • Transforming Growth Factor beta
  • Collagen
  • Creatinine