SND p102 was first described as a transcriptional co-activator, and subsequently determined to be a co-regulator of Pim-1, STAT6 and STAT5. We previously reported that SND p102 expression was increased in high glucose-treated mesangial cells (MCs) and plays a role in the extracellular matrix (ECM) accumulation of MCs by regulating the activation of RAS. In this study, we further examined the roles of SND p102 in diabetic nephropathy (DN)-induced glomerulosclerosis. Rats were injected with STZ (50 mg/kg, ip) to induce diabetes. MCs or isolated glomeruli were cultured in normal glucose (NG, 5.5 mmol/L)- or high glucose (HG, 25 mmol/L)-containing DMEM. We found that SND p102 expression was significantly increased in the diabetic kidneys, as well as in HG-treated isolated glomeruli and MCs. In addition, HG treatment induced significant fibrotic changes in MCs evidenced by enhanced protein expression of TGF-β, fbronectin and collagen IV, and significantly increased the proliferation of MCs. We further revealed that overexpression of SND p102 significantly increased the protein expression of angiotensin II (Ang II) type 1 receptor (AT1R) in MCs by increasing its mRNA levels via directly targeting the AT1R 3'-UTR, which resulted in activation of the ERK/Smad3 signaling and subsequently promoted the up-regulation of fbronectin, collagen IV, and TGF-β in MCs, as well as the cell proliferation. These results demonstrate that SND p102 is a key regulator of AT1R-mediating ECM synthesis and cell proliferation in MCs. Thus, small molecule inhibitors of SND p102 may be a novel therapeutic strategy for DN.

中文翻译：

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SND p102通过AT1R / ERK / Smad3途径促进大鼠肾小球系膜细胞中细胞外基质的积累和细胞增殖。

SND p102首先被描述为转录共激活子，随后被确定为Pim-1，STAT6和STAT5的共调节子。我们先前曾报道SND p102表达在高葡萄糖处理的肾小球系膜细胞（MCs）中增加，并通过调节RAS的激活在MCs的细胞外基质（ECM）积累中发挥作用。在这项研究中，我们进一步检查了SND p102在糖尿病肾病（DN）诱导的肾小球硬化中的作用。给大鼠注射STZ（50 mg / kg，ip）诱导糖尿病。MCs或分离的肾小球在含正常葡萄糖（NG，5.5 mmol / L）或高葡萄糖（HG，25 mmol / L）的DMEM中培养。我们发现SND p102表达在糖尿病肾脏，以及经HG治疗的孤立肾小球和MC中均显着增加。此外，HG处理可诱导MCs发生明显的纤维化变化，其表现为TGF-β，纤连蛋白和胶原IV的蛋白表达增强，并显着增加MCs的增殖。我们进一步揭示SND p102的过表达通过直接靶向AT1R 3'-UTR来增加其mRNA水平，从而显着增加了MC中血管紧张素II（Ang II）1型受体（AT1R）的蛋白表达，从而激活了ERK。 / Smad3信号传导，并随后促进MC中纤连蛋白，胶原蛋白IV和TGF-β的上调以及细胞增殖。这些结果表明，SND p102是介导AT1R介导的ECM合成和MC细胞增殖的关键调节剂。因此，SND p102的小分子抑制剂可能是DN的新型治疗策略。