Abstract：
Diabetic nephropathy (DN) is one of the common microvascular complications in diabetic patients. Marrow mesenchymal stem cells (MSCs) have attracted attention in DN therapy but the underlying mechanism remains unclear. Here, we show that MSC administration alleviates high glucose (HG)-induced human kidney tubular epithelial cell (HK-2 cell) injury and ameliorates renal injury in DN mice. We identify that Smad2/3 is responsible for MSCs-regulated DN progression. The activity of Smad2/3 was predominantly upregulated in HG-induced HK-2 cell and DN mice and suppressed with MSC administration. Activation of Smad2/3 via transforming growth factor-β1 (TGF-β1) administration abrogates the protective effect of MSCs on HG-induced HK-2 cell injury and renal injury of DN mice. Smad2/3 has been reported to interact with methyltransferase of N6-methyladenosine (m6A) complex and we found a methyltransferase, Wilms\' tumor 1-associating protein (WTAP), is involved in MSCs-Smad2/3-regulated DN development. Moreover, WTAP overexpression abrogates the improvement of MSCs on HG-induced HK-2 cell injury and renal injury of DN mice. Subsequently, α-enolase (ENO1) is the downstream target of WTAP-mediated m6A modification and contributes to the MSCs-mediated regulation. Collectively, these findings reveal a molecular mechanism in DN progression and indicate that Smad2/3/WTAP/ENO1 may present a target for MSCs-mediated DN therapy.
摘要：
糖尿病肾病(DN)是糖尿病患者常见的微血管并发症之一。骨髓间充质干细胞（MSCs）在DN治疗中受到广泛关注，但其机制尚不清楚。这里,我们证明MSC可以减轻高糖（HG）诱导的人肾小管上皮细胞（HK-2细胞）损伤，并改善DN小鼠的肾损伤。我们确定Smad2/3负责MSC调节的DN进展。Smad2/3的活性在HG诱导的HK-2细胞和DN小鼠中主要上调，并被MSC抑制。通过转化生长因子-β1（TGF-β1）激活Smad2/3可以消除MSCs对HG诱导的HK-2细胞损伤和DN小鼠肾脏损伤的保护作用。据报道，Smad2/3与N6-甲基腺苷（m6A）复合物的甲基转移酶相互作用，我们发现了甲基转移酶，Wilms\'肿瘤1相关蛋白（WTAP），参与MSCs-Smad2/3调控的DN发育。此外，WTAP过表达消除了MSCs对HG诱导的HK-2细胞损伤和DN小鼠肾损伤的改善作用。随后，α-烯醇化酶（ENO1）是WTAP介导的m6A修饰的下游靶标，并有助于MSC介导的调节。总的来说，这些发现揭示了DN进展的分子机制,并表明Smad2/3/WTAP/ENO1可能是MSCs介导的DN治疗的靶点.
