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Glomerular VEGF resistance induced by PKC?/SHP-1 activation and contribution to diabetic nephropathy.

ABSTRACT: This study characterizes the effect of glucose-induced activation of protein kinase C? (PKC?) and Src homology-2 domain-containing phosphatase-1 (SHP-1) expression on vascular endothelial growth factor (VEGF) actions in glomerular podocytes in cultures and in glomeruli of diabetic rodents. Elevation of glucose levels induced PKC? and p38 mitogen-activated protein kinase (p38 MAPK) to increase SHP-1 expression, increased podocyte apoptosis, and inhibited VEGF activation in podocytes and glomerular endothelial cells. The adverse effects of high glucose levels can be negated by molecular inhibitors of PKC?, p38MAPK, and SHP-1 and only partially reduced by antioxidants and nuclear factor-?B (NF-?B) inhibitor. Increased PKC? activation and SHP-1 expression correlated with loss of VEGF signaling and podocyte numbers in the glomeruli of diabetic rats and mice. In contrast, diabetic PKC?-knockout (Prkcd(-/-)) mice did not exhibit activation of p38 MAPK and SHP-1 or inhibition of VEGF signaling in renal glomeruli. Functionally, diabetic Prkcd(-/-) mice had decreased expressions of TGF?, VEGF, and extracellular matrix and less albuminuria than diabetic Prkcd(+/+) mice. Hyperglycemia and diabetes can cause glomerular podocyte apoptosis and endothelial dysfunction partly due to increased PKC?/p38 MAPK activation and the expression of SHP-1 to cause VEGF resistance, independent of NF-?B activation.

SUBMITTER: Mima A

PROVIDER: S-EPMC3382088 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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Glomerular VEGF resistance induced by PKCδ/SHP-1 activation and contribution to diabetic nephropathy.

Mima Akira A Kitada Munehiro M Geraldes Pedro P Li Qian Q Matsumoto Motonobu M Mizutani Koji K Qi Weier W Li Chenzhong C Leitges Michael M Rask-Madsen Christian C King George L GL

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20120412 7

This study characterizes the effect of glucose-induced activation of protein kinase Cδ (PKCδ) and Src homology-2 domain-containing phosphatase-1 (SHP-1) expression on vascular endothelial growth factor (VEGF) actions in glomerular podocytes in cultures and in glomeruli of diabetic rodents. Elevation of glucose levels induced PKCδ and p38 mitogen-activated protein kinase (p38 MAPK) to increase SHP-1 expression, increased podocyte apoptosis, and inhibited VEGF activation in podocytes and glomerula ...[more]

PMID: 22499584

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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

Glomerular VEGF resistance induced by PKC?/SHP-1 activation and contribution to diabetic nephropathy.

Publications

Glomerular VEGF resistance induced by PKCδ/SHP-1 activation and contribution to diabetic nephropathy.

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