Fractalkine and its receptor mediate extracellular matrix accumulation in diabetic nephropathy in mice

K. H. Song, J. Park, J. H. Park, R. Natarajan, H. Ha

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Aims/hypothesis: Fractalkine (FKN) is a unique chemokine that works as a chemoattractant and an adhesion molecule. Previous studies have demonstrated that FKN plays a role in ischaemic and protein-overload renal injury via its cognate receptor chemokine (C-X3-C motif) receptor 1 (CX3CR1). However, involvement of the FKN/CX3CR1 system in diabetic nephropathy remains unclear. We examined the role of FKN/CX3CR1 in diabetic mice and mouse mesangial cells (MMCs). Methods: Streptozotocin (50 mg kg-1 day-1) was intraperitoneally administered for 5 days to male Cx3cr1-knockout (KO) mice and wild-type (WT) mice. MMCs transfected with Fkn (also known as Cx3cl1) or Cx3cr1 siRNA, respectively, were used to elucidate the role of FKN/CX3CR1 in extracellular matrix (ECM) synthesis. Results: At 12 weeks, diabetic Cx3cr1 KO mice showed no significant changes in plasma glucose, but markers of renal inflammation, fibrosis and ECM, such as the fractional mesangial area, fibronectin and collagen, were significantly lower in diabetic Cx3cr1 KO mice compared with diabetic WT mice. High glucose, oleic acid and TGF-β1 stimulated FKN and CX3CR1 expression, together with the expression of ECM proteins in MMCs, but the effects were significantly attenuated by Fkn or Cx3cr1 siRNA. More importantly, FKN itself increased mesangial ECM through CX3CR1 and subsequent activation of reactive oxygen species and mitogen-activated protein kinases. A neutralising TGF-β antibody inhibited FKN/CX3CR1 in MMCs treated with diabetic stimuli and decreased FKN-induced ECM accumulation. Conclusions/interpretation: These results demonstrate that FKN/CX3CR1 may play an important role in diabetic renal injury through upregulation of ECM synthesis and could therefore be a therapeutic target for preventing diabetic nephropathy.

Original languageEnglish
Pages (from-to)1661-1669
Number of pages9
JournalDiabetologia
Volume56
Issue number7
DOIs
StatePublished - Jul 2013

Keywords

  • CX3CR1
  • Diabetic nephropathy
  • Fractalkine
  • Glomerulosclerosis
  • Mesangial cells

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