Reduced Adenosine Uptake and Its Contribution to Signaling that Mediates Profibrotic Activation in Renal Tubular Epithelial Cells: Implication in Diabetic Nephropathy.
Reduced Adenosine Uptake and Its Contribution to Signaling that Mediates Profibrotic Activation in Renal Tubular Epithelial Cells: Implication in Diabetic Nephropathy.
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DOI：
10.1371/journal.pone.0147430
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
San Martín R
中科院分区：
文献类型：
--
作者：
Kretschmar C;Oyarzún C;Villablanca C;Jaramillo C;Alarcón S;Perez G;Díaz-Encarnación MM;Pastor-Anglada M;Garrido W;Quezada C;San Martín R
核苷水平的改变可能通过腺苷受体与致病信号传导有关。我们假设腺苷失调有助于糖尿病肾病的纤维化。我们的研究结果表明，高葡萄糖水平和实验性糖尿病通过近端小管细胞的平衡核苷转运蛋白1 （ENT1）降低摄取活性。此外，糖尿病大鼠血浆中腺苷含量的增加与肾纤维化标志物之间存在相关性。在细胞水平上，HK2细胞暴露于高糖、TGF-β和通用腺苷受体激动剂NECA，诱导了纤维化细胞活化标志物α-SMA和纤维连接蛋白的表达。这些影响可以通过在体外使用腺苷A3受体亚型的选择性拮抗剂来避免。此外，A3受体拮抗剂可阻止糖尿病大鼠肾脏纤维化标志物α-SMA的诱导。总之，我们证实了嘌呤能信号在实验性糖尿病肾病肾纤维化中的作用。
Altered nucleoside levels may be linked to pathogenic signaling through adenosine receptors. We hypothesized that adenosine dysregulation contributes to fibrosis in diabetic kidney disease. Our findings indicate that high glucose levels and experimental diabetes decreased uptake activity through the equilibrative nucleoside transporter 1 (ENT1) in proximal tubule cells. In addition, a correlation between increased plasma content of adenosine and a marker of renal fibrosis in diabetic rats was evidenced. At the cellular level, exposure of HK2 cells to high glucose, TGF-β and the general adenosine receptor agonist NECA, induced the expression of profibrotic cell activation markers α-SMA and fibronectin. These effects can be avoided by using a selective antagonist of the adenosine A3 receptor subtype in vitro. Furthermore, induction of fibrosis marker α-SMA was prevented by the A3 receptor antagonist in diabetic rat kidneys. In conclusion, we evidenced the contribution of purinergic signaling to renal fibrosis in experimental diabetic nephropathy.