Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710005, China.
Department of Clinical Laboratory, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710005, China.
Pharmacol Res. 2021 Jul;169:105630. doi: 10.1016/j.phrs.2021.105630. Epub 2021 Apr 29.
DPP8 and DPP9 have been demonstrated to play important roles in multiple diseases. Evidence for increased gene expression of DPP8 and DPP9 in tubulointerstitium was found to be associated with the decline of kidney function in chronic kidney disease (CKD) patients, which was observed in the Nephroseq human database. To examine the role of DPP8 and DPP9 in the tubulointerstitial injury, we determined the efficacy of DPP8 and DPP9 on epithelial-to-mesenchymal transition (EMT) and tubulointerstitial fibrosis (TIF) as well as the underlying mechanisms.
We conducted the immunofluorescence of DPP8 and DPP9 in kidney biopsy specimens of CKD patients, established unilateral ureteral obstruction (UUO) animal model, treated with TC-E5007 (a specific inhibitor of both DPP8 and DPP9) or Saxagliptin (positive control) or saline, and HK-2 cells model.
We observed the significantly increased expression of DPP8 and DPP9 in the renal proximal tubule epithelial cells of CKD patients compared to the healthy control subjects. DPP8/DPP9 inhibitor TC-E5007 could significantly attenuate the EMT and extracellular matrix (ECM) synthesis in UUO mice, all these effects were mediated via interfering with the TGF-β1/Smad signaling. TC-E5007 treatment also presented reduced renal inflammation and improved renal function in the UUO mice compared to the placebo-treated UUO group. Furthermore, the siRNA for DPP8 and DPP9, and TC-E5007 treatment decreased EMT- and ECM-related proteins in TGF-β1-treated HK-2 cells respectively, which could be reversed significantly by transduction with lentivirus-DPP8 and lentivirus-DPP9.
These data obtained provide evidence that the DPP8 and DPP9 could be potential therapeutic targets against TIF.
DPP8 和 DPP9 已被证明在多种疾病中发挥重要作用。在 Nephroseq 人类数据库中发现，肾小管间质中 DPP8 和 DPP9 基因表达增加与慢性肾脏病 (CKD) 患者肾功能下降有关。为了研究 DPP8 和 DPP9 在肾小管间质损伤中的作用，我们确定了 DPP8 和 DPP9 对上皮间质转化 (EMT) 和肾小管间质纤维化 (TIF) 的作用及其潜在机制。
我们对 CKD 患者的肾活检标本进行了 DPP8 和 DPP9 的免疫荧光检测，建立了单侧输尿管梗阻 (UUO) 动物模型，用 TC-E5007（一种同时抑制 DPP8 和 DPP9 的抑制剂）或沙格列汀（阳性对照）或生理盐水进行处理，并建立了 HK-2 细胞模型。
我们观察到与健康对照组相比，CKD 患者的肾脏近端小管上皮细胞中 DPP8 和 DPP9 的表达明显增加。DPP8/DPP9 抑制剂 TC-E5007 可显著减轻 UUO 小鼠的 EMT 和细胞外基质 (ECM) 合成，所有这些作用均通过干扰 TGF-β1/Smad 信号转导介导。与安慰剂处理的 UUO 组相比，TC-E5007 治疗还可减少 UUO 小鼠的肾脏炎症并改善其肾功能。此外，DPP8 和 DPP9 的 siRNA 以及 TC-E5007 处理分别降低了 TGF-β1 处理的 HK-2 细胞中的 EMT 和 ECM 相关蛋白，而用慢病毒-DPP8 和慢病毒-DPP9 转导可显著逆转这些作用。
这些数据为 DPP8 和 DPP9 可能成为 TIF 潜在治疗靶点提供了证据。
