Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy.
Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy.
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高血糖引起的细胞凋亡发生在许多血管细胞中，是引发糖尿病病理的关键。在视网膜中，周细胞凋亡是由高血糖引起的最特殊的血管病理，由于未知的机制，它与PDGF作用的丧失有关。我们的研究表明，高血糖持续激活PKCδ和p38α MAPK，增加新靶点SHP-1的表达，导致PDGF受体-β去磷酸化和作用，增加周细胞凋亡，不依赖于NF-κB。这些发现也在糖尿病小鼠视网膜中观察到，胰岛素不能逆转糖尿病小鼠视网膜的正常血糖。与糖尿病对照组不同，糖尿病Prkcd−/−小鼠没有表现出p38α MAPK/SHP-1激活、PDGF抵抗或脱细胞毛细血管。糖尿病还可诱导PKCδ/p38α MAPK/SHP-1在脑周细胞和肾皮质活化，这些发现阐明了高血糖诱导PDGF抵抗和增加血管细胞凋亡导致糖尿病血管并发症的新途径。
Cellular apoptosis induced by hyperglycemia occurs in many vascular cells and is critical to initiate diabetic pathologies. In the retina, pericyte apoptosis, the most specific vascular pathology attributed to hyperglycemia, is linked to the loss of PDGF actions due to unknown mechanisms. Our study demonstrated that hyperglycemia persistently activated PKCδ and p38α MAPK to increase the expression of a novel target, SHP-1, leading to PDGF receptor-β dephosphorylation and actions, and increased pericyte apoptosis, independent of NF-κB. These findings were also observed in diabetic mouse retinas, which were not reversed by achieving normoglycemia with insulin. Unlike diabetic controls, diabetic Prkcd−/− mice did not exhibit p38α MAPK/SHP-1 activation, PDGF resistance or acellular capillaries. Since PKCδ/p38α MAPK/SHP-1 activation are also induced in the brain pericytes and renal cortex by diabetes, these findings have elucidated a new pathway by which hyperglycemia can induce PDGF resistance and increase vascular cell apoptosis to cause diabetic vascular complications.