首页> 外文期刊>The biochemical journal >Role of the Janus kinase (JAK)/signal transducters and activators of transcription (STAT) cascade in advanced glycation end-product-induced cellular mitogenesis in NRK-49F cells
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Role of the Janus kinase (JAK)/signal transducters and activators of transcription (STAT) cascade in advanced glycation end-product-induced cellular mitogenesis in NRK-49F cells

机译:Janus激酶(JAK)/信号转导子和转录激活子(STAT)级联在NRK-49F细胞中晚期糖基化终产物诱导的细胞有丝分裂中的作用

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pAdvanced glycation end product (AGE) is important in the pathogenesis of diabetic nephropathy, which is characterized by cellular hypertrophy/hyperplasia leading to renal fibrosis. However, the signal transduction pathways of AGE remain poorly understood. The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway has been associated with cellular proliferation in some extra-renal cells. Because interstitial fibroblast proliferation might be important in renal fibrosis, we studied the role of the JAK/STAT pathway in NRK-49F (normal rat kidney fibroblast) cells cultured in AGE/BSA and non-glycated BSA. We showed that AGE dose-dependently (10-200 iμ/ig/ml) increased cellular mitogenesis in NRK-49F cells at 5 and 7 days. However, cellular mitogenesis was unaffected by the simultaneous presence of BSA. Regarding the JAK/STAT pathway, AGE (100 iμ/ig/ml) induced tyrosine phosphorylation of JAK2 (but not JAK1, JAK3 or TYK2) at 15-60 min; it also induced the tyrosine phosphorylation of STAT1 and STAT3 at 1-2 h and 0.5-4 h respectively. Being a transcription factor, AGE also increased the DNA-binding activities of STAT1 and STAT3 AG-490 (a specific JAK2 inhibitor) (5 iμ/iM) inhibited tyrosine phosphorylation of JAK2 and the DNA-binding activities of STAT1 and STAT3. The same results were obtained by using specific ‘decoy’ oligodeoxynucleotides (ODNs) that prevented STAT1 and STAT3 from binding to DNA. Meanwhile, the STAT1 or STAT3 decoy ODN and AG-490 were effective in reversing AGE-induced cellular mitogenesis. We concluded that the JAK2-STAT1/STAT3 signal transduction pathway is necessary for AGE-induced cellular mitogenesis in NRK-49F cells./p
机译:>晚期糖基化终产物(AGE)在糖尿病性肾病的发病机理中很重要,其特征是细胞肥大/增生导致肾纤维化。但是,AGE的信号转导途径仍然知之甚少。 Janus激酶(JAK)/信号转导子和转录激活子(STAT)通路与某些肾外细胞的细胞增殖有关。因为间质成纤维细胞增殖可能在肾纤维化中很重要,所以我们研究了JAK / STAT通路在AGE / BSA和非糖化BSA培养的NRK-49F(正常大鼠肾成纤维细胞)细胞中的作用。我们显示AGE剂量依赖性地(10-200μg/ ml)在5天和7天时会增加NRK-49F细胞的细胞有丝分裂发生。但是,细胞有丝分裂不受BSA同时存在的影响。关于JAK / STAT途径,AGE(100μg/ ml)在15-60分钟诱导JAK2(而不是JAK1,JAK3或TYK2)的酪氨酸磷酸化。它也分别在1-2 h和0.5-4 h诱导STAT1和STAT3的酪氨酸磷酸化。 AGE作为一种转录因子,还增加了STAT1和STAT3 AG-490(一种特定的JAK2抑制剂)(5μM)的DNA结合活性,抑制了JAK2的酪氨酸磷酸化,并抑制了JAK2的DNA结合活性。 STAT1和STAT3。使用特定的“诱饵”寡脱氧核苷酸(ODN)可防止STAT1和STAT3与DNA结合,从而获得相同的结果。同时,STAT1或STAT3诱饵ODN和AG-490可有效逆转AGE诱导的细胞有丝分裂。结论:JAK2-STAT1 / STAT3信号转导通路是AGE诱导NRK-49F细胞有丝分裂的必要途径。

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