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

ABSTRACT: 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).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.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-?1 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-? antibody inhibited FKN/CX3CR1 in MMCs treated with diabetic stimuli and decreased FKN-induced ECM accumulation.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.

SUBMITTER: Song KH

PROVIDER: S-EPMC4737593 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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

Song K H KH Park J J Park J H JH Natarajan R R Ha H H

Diabetologia 20130419 7

<h4>Aims/hypothesis</h4>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).<h4>Methods</h4>Streptozotocin ...[more]

PMID: 23604552

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Project description:Diabetic nephropathy is a leading cause of end-stage renal disease globally. The vital role of circular RNAs (circRNAs) has been reported in diabetic nephropathy progression, but the molecular mechanism linking diabetic nephropathy to circRNAs remains elusive. In this study, we investigated the significant function of circ-AKT3/miR-296-3p/E-cadherin regulatory network on the extracellular matrix accumulation in mesangial cells in diabetic nephropathy. The expression of circ-AKT3 and fibrosis-associated proteins, including fibronectin, collagen type I and collagen type IV, was assessed via RT-PCR and Western blot analysis in diabetic nephropathy animal model and mouse mesangial SV40-MES13 cells. Luciferase reporter assays were used to investigate interactions among E-cadherin, circ-AKT3 and miR-296-3p in mouse mesangial SV40-MES13 cells. Cell apoptosis was evaluated via flow cytometry. The level of circ-AKT3 was significantly lower in diabetic nephropathy mice model group and mouse mesangial SV40-MES13 cells treated with high-concentration (25 mmol/L) glucose. In addition, circ-AKT3 overexpression inhibited the level of fibrosis-associated protein, such as fibronectin, collagen type I and collagen type IV. Circ-AKT3 overexpression also inhibited the apoptosis of mouse mesangial SV40-MES13 cells treated with high glucose. Luciferase reporter assay and bioinformatics tools identified that circ-AKT3 could act as a sponge of miR-296-3p and E-cadherin was the miR-296-3p direct target. Moreover, circ-AKT3/miR-296-3p/E-cadherin modulated the extracellular matrix of mouse mesangial cells in high-concentration (25 mmol/L) glucose, inhibiting the synthesis of related extracellular matrix protein. In conclusion, circ-AKT3 inhibited the extracellular matrix accumulation in diabetic nephropathy mesangial cells through modulating miR-296-3p/E-cadherin signals, which might offer novel potential opportunities for clinical diagnosis targets and therapeutic biomarkers for diabetic nephropathy.

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Dataset Information

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

Publications

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

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