Dataset Information

Osteopontin plays a critical role in interstitial fibrosis but not glomerular sclerosis in diabetic nephropathy.

ABSTRACT:

Background/aims

Osteopontin (OPN) has been implicated in the pathology of several renal conditions. The aim of this study was to clarify the roles of OPN in diabetic nephropathy.

Methods

Diabetes mellitus (DM) was induced in wild-type (WT) and OPN knockout (KO) mice by injecting streptozotocin. The mice were killed 20 weeks after induction of DM and their kidneys removed.

Results

Renal mRNA expression of OPN was increased in WT-DM mice compared to WT-sham mice. Immunohistochemistry showed high levels of OPN expression in the proximal tubules of WT-DM mice. Kidney weight and urinary albumin excretion increased to similar levels in the WT-DM and KO-DM mice. Interstitial fibrosis was increased in WT-DM mice compared to KO-DM mice. However, there were no differences in the degree of mesangial expansion or glomerular hypertrophy between the two groups. F4/80-positive cells (macrophages) and FSP-1-positive cells (fibroblasts) showed significantly higher infiltration in WT-DM mice than in KO-DM mice. Renal mRNA expression of NADPH oxidase subunits and urinary 8-isoprostane excretion were also increased in WT-DM mice.

Conclusions

These results indicated that OPN is a key molecule that induces interstitial fibrosis in the diabetic kidney, but does not induce glomerular sclerosis.

SUBMITTER: Nagao T

PROVIDER: S-EPMC3346163 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Publications

Osteopontin plays a critical role in interstitial fibrosis but not glomerular sclerosis in diabetic nephropathy.

Nagao Tomoaki T Okura Takafumi T Irita Jun J Jotoku Masanori M Enomoto Daijiro D Desilva Veena Rasika VR Miyoshi Ken-Ichi K Kurata Mie M Matsui Yutaka Y Uede Toshimitsu T Higaki Jitsuo J

Nephron extra 20120101 1

<h4>Background/aims</h4>Osteopontin (OPN) has been implicated in the pathology of several renal conditions. The aim of this study was to clarify the roles of OPN in diabetic nephropathy.<h4>Methods</h4>Diabetes mellitus (DM) was induced in wild-type (WT) and OPN knockout (KO) mice by injecting streptozotocin. The mice were killed 20 weeks after induction of DM and their kidneys removed.<h4>Results</h4>Renal mRNA expression of OPN was increased in WT-DM mice compared to WT-sham mice. Immunohistoc ...[more]

PMID: 22619671

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Project description:BACKGROUND:Glomerular endothelium dysfunction, which plays a crucial role in the pathogenesis of early diabetic nephropathy, might be caused by circulating metabolic abnormalities. Platelet microparticles, extracellular vesicles released from activated platelets, have recently emerged as a novel regulator of vascular dysfunction. METHODS:We studied the effects of platelet microparticles on glomerular endothelial injury in early diabetic nephropathy in rats with streptozotocin-induced diabetes and primary rat glomerular endothelial cells. Isolated platelet microparticles were measured by flow cytometry. RESULTS:Plasma platelet microparticles were significantly increased in diabetic rats, an effect inhibited in aspirin-treated animals. In cultured glomerular endothelial cells, platelet microparticles induced production of reactive oxygen species, decreased nitric oxide levels, inhibited activities of endothelial nitric oxide synthase and SOD, increased permeability of the glomerular endothelium barrier, and reduced thickness of the endothelial surface layer. Conversely, inhibition of platelet microparticles in vivo by aspirin improved glomerular endothelial injury. Further analysis showed that platelet microparticles activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in glomerular endothelial cells; inhibition of the mTORC1 pathway by rapamycin or raptor siRNA significantly protected against microparticle-induced glomerular endothelial injury in vivo and in vitro. Moreover, platelet microparticle-derived chemokine ligand 7 (CXCL7) contributed to glomerular endothelial injury, and antagonizing CXCL7 using CXCL7-neutralizing antibody or blocking CXCL7 receptors with a competitive inhibitor of CXCR1 and CXCR2 dramatically attenuated such injury. CONCLUSIONS:These findings demonstrate a pathogenic role of platelet microparticles in glomerular endothelium dysfunction, and suggest a potential therapeutic target, CXCL7, for treatment of early diabetic nephropathy.

Dataset Information

Osteopontin plays a critical role in interstitial fibrosis but not glomerular sclerosis in diabetic nephropathy.

Background/aims

Methods

Results

Conclusions

Publications

Osteopontin plays a critical role in interstitial fibrosis but not glomerular sclerosis in diabetic nephropathy.

Similar Datasets

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