title: Glomerular VEGF resistance induced by PKCδ/SHP-1 activation and contribution to diabetic nephropathy.
abstract: 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 glomerular endothelial cells. The adverse effects of high glucose levels can be negated by molecular inhibitors of PKCδ, p38MAPK, and SHP-1 and only partially reduced by antioxidants and nuclear factor-κB (NF-κB) inhibitor. Increased PKCδ 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 PKCδ-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 TGFβ, 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 PKCδ/p38 MAPK activation and the expression of SHP-1 to cause VEGF resistance, independent of NF-κB activation.
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Mima
authors.forename: Munehiro
authors.initials: M
authors.lastname: Kitada
authors.forename: Pedro
authors.initials: P
authors.lastname: Geraldes
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Motonobu
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Koji
authors.initials: K
authors.lastname: Mizutani
authors.forename: Weier
authors.initials: W
authors.lastname: Qi
authors.forename: Chenzhong
authors.initials: C
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Christian
authors.initials: C
authors.lastname: Rask-Madsen
authors.forename: George L
authors.initials: GL
authors.lastname: King
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005947:Glucose / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C467498:vascular endothelial growth factor A, rat; C497259:Prkcd protein, mouse; C497260:Prkcd protein, rat; D040301:Vascular Endothelial Growth Factor Receptor-2; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; C509250:Ptpn6 protein, rat; D005947:Glucose