Deletion of platelet-derived growth factor receptor-β improves diabetic nephropathy in Ca2+/calmodulin-dependent protein kinase IIα (Thr286Asp) transgenic mice
Deletion of platelet-derived growth factor receptor-β improves diabetic nephropathy in Ca2+/calmodulin-dependent protein kinase IIα (Thr286Asp) transgenic mice
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DOI：
10.1007/s00125-011-2270-x
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发表时间：
2011-11-01
期刊：
影响因子：
8.2
通讯作者：
Sasahara, M.
中科院分区：
文献类型：
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作者：
Suzuki, H.;Usui, I.;Sasahara, M.
糖尿病动物肾小球和肾小管中血小板衍生生长因子受体-β(PDGFR-β)信号的激活增加。在这项研究中，我们研究了PDGFR-β信号在糖尿病肾病发生发展中的作用。我们最近获得了胰腺β细胞特异性钙/钙调素依赖性蛋白激酶IIα(Thr286Asp)转基因小鼠(CaMKIIα小鼠)，它们的血糖水平非常高，高达55.5 mmol/L，表现出糖尿病肾病的特征。将这些小鼠与条件基因敲除小鼠进行杂交，在这些小鼠中，PDGFR-beta(也称为PDGFRb)在出生后被删除。在10周龄和16周龄的CaMKIIα小鼠中，观察了PDGFR-β基因缺失对糖尿病肾病的影响。在16周龄时，观察了糖尿病肾病的指标，如尿白蛋白/肌酐比率、肾脏重量/体重比率和系膜面积/肾小球面积比率。出生后PDGFR-β基因缺失显著降低尿白蛋白/肌酐比值和系膜面积/肾小球面积比值，但不影响血糖浓度。此外，PDGFR-β基因缺失使CaMKIIα小鼠肾脏氧化应激增加，表现为尿8-羟基脱氧鸟苷(8-OHdG)排泄量增加，NAD(P)H氧化酶4(NOX4)、谷胱甘肽过氧化物酶1(GPX1)和锰超氧化物歧化酶(MnSOD)表达增加。PDGFR-β信号通路的激活有助于糖尿病肾病的进展，并增加氧化应激和系膜扩张。
The activation of platelet-derived growth factor receptor-beta (PDGFR-beta) signalling is increased in the glomeruli and tubules of diabetic animals. In this study, we examined the role of PDGFR-beta signalling during the development of diabetic nephropathy.We recently generated pancreatic beta cell-specific Ca2+/calmodulin-dependent protein kinase II alpha (Thr286Asp) transgenic mice (CaMKII alpha mice), which show very high plasma glucose levels up to 55.5 mmol/l and exhibit the features of diabetic nephropathy. These mice were crossed with conditional knockout mice in which Pdgfr-beta (also known as Pdgfrb) was deleted postnatally. The effect of the deletion of the Pdgfr-beta gene on diabetic nephropathy in CaMKII alpha mice was evaluated at 10 and 16 weeks of age.The plasma glucose concentrations and HbA(1c) levels were elevated in the CaMKII alpha mice from 4 weeks of age. Variables indicative of diabetic nephropathy, such as an increased urinary albumin/creatinine ratio, kidney weight/body weight ratio and mesangial area/glomerular area ratio, were observed at 16 weeks of age. The postnatal deletion of the Pdgfr-beta gene significantly decreased the urinary albumin/creatinine ratio and mesangial area/glomerular area ratio without affecting the plasma glucose concentration. Furthermore, the increased oxidative stress in the kidneys of the CaMKII alpha mice as shown by the increased urinary 8-hydroxydeoxyguanosine (8-OHdG) excretion and the increased expression of NAD(P)H oxidase 4 (NOX4), glutathione peroxidase 1 (GPX1) and manganese superoxide dismutase (MnSOD) was decreased by Pdgfr-beta gene deletion.The activation of PDGFR-beta signalling contributes to the progress of diabetic nephropathy, with an increase in oxidative stress and mesangial expansion in CaMKII alpha mice.