Department of Endocrinology, Fuzong Clinical Medical College of Fujian Medical University, No.156 Xierhuan Road, FuZhou, Fujian, 350000, China.
Central Laboratory, Fuzong Clinical Medical College of Fujian Medical University, No.156 Xierhuan Road, FuZhou, Fujian, 350000, China.
Biochem Biophys Res Commun. 2021 Apr 23;550:62-69. doi: 10.1016/j.bbrc.2020.12.030. Epub 2021 Mar 5.
Diabetic nephropathy (DN) is a common complication of diabetes, and a leading cause of end-stage renal disease. However, the pathogenesis that contributes to DKD is still not fully understood. Protein tyrosine phosphatase non-receptor type 14 (PTPN14), a non receptor tyrosine phosphatase, has numerous cellular events, such as inflammation and cell death. But its potential on DKD has not been investigated yet. In this study, we found that PTPN14 expression was markedly up-regulated in kidney samples of DKD patients, which were confirmed in diabetic mice and were clearly localized in glomeruli. The diabetic mouse model was established using streptozotocin (STZ) in wild type (WT) or PTPN knockout (KO) mice. After, STZ challenge, STZ mice displayed improved kidney functions. The results also showed that STZ-induced histological changes and podocyte injury in renal tissues, which were effectively alleviated by PTPN14 deletion. Moreover, PTPN14 deficiency significantly mitigated inflammatory response and fibrosis in glomeruli of STZ-challenged mice through restraining the activation of nuclear factor-κB (NF-κB) and transforming growth factor (TGF)-β1 signaling pathways, respectively. The inhibitory effects of PTPN14 suppression on inflammation and fibrosis were confirmed in high glucose (HG)-incubated podocytes. We further found that thyroid receptor interactor protein 6 (TRIP6) expression was dramatically up-regulated in glomeruli of STZ-challenged mice, and was abolished by PTPN14 deletion, which was confirmed in HG-treated podocytes with PTPN14 knockdown. Intriguingly, our in vitro studies showed that PTPN14 directly interacted with TRIP6. Of note, over-expressing TRIP6 markedly abrogated the effects of PTPN14 silence to restrict inflammatory response and fibrosis in HG-incubated podocytes. Taken together, our findings demonstrated that targeting PTPN14 may provide feasible therapies for DKD treatment.
糖尿病肾病（DN）是糖尿病的常见并发症，也是终末期肾病的主要原因。然而，导致 DKD 的发病机制尚未完全阐明。蛋白酪氨酸磷酸酶非受体型 14（PTPN14）是一种非受体酪氨酸磷酸酶，参与多种细胞事件，如炎症和细胞死亡。但其在 DKD 中的潜在作用尚未得到研究。在这项研究中，我们发现 PTPN14 在 DKD 患者的肾脏样本中表达明显上调，在糖尿病小鼠和肾小球中也得到了证实。我们使用链脲佐菌素（STZ）在野生型（WT）或 PTPN 敲除（KO）小鼠中建立了糖尿病小鼠模型。STZ 处理后，STZ 小鼠的肾脏功能得到改善。结果还表明，STZ 诱导的组织学变化和肾脏组织中的足细胞损伤，通过 PTPN14 缺失得到有效缓解。此外，PTPN14 缺失通过分别抑制核因子-κB（NF-κB）和转化生长因子（TGF）-β1 信号通路的激活，显著减轻 STZ 处理小鼠肾小球中的炎症反应和纤维化。在高糖（HG）孵育的足细胞中，证实了 PTPN14 抑制对炎症和纤维化的抑制作用。我们进一步发现，甲状腺受体相互作用蛋白 6（TRIP6）在 STZ 处理的小鼠肾小球中表达明显上调，并且在 PTPN14 敲低的 HG 处理的足细胞中被 PTPN14 缺失所消除。有趣的是，我们的体外研究表明 PTPN14 与 TRIP6 直接相互作用。值得注意的是，过表达 TRIP6 显著减弱了 PTPN14 沉默对 HG 孵育的足细胞中炎症反应和纤维化的限制作用。总之，我们的研究结果表明，针对 PTPN14 可能为 DKD 的治疗提供可行的治疗方法。
