Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, 920-0293, Japan.
Mitsubishi Tanabe Pharma Corporation Ikuyaku, Integrated Value Development Division, Tokyo, Japan.
Sci Rep. 2019 May 17;9(1):7519. doi: 10.1038/s41598-019-43730-5.
Diabetic kidney disease (DKD) is appeared to be higher risk of declining kidney function compared to non-diabetic kidney disease with same magnitude of albuminuria. Epithelial-mesenchymal transition (EMT) program of tubular epithelial cells (TECs) could be important for the production of the extracellular matrix in the kidney. Caveolin-1 (CAV1), dipeptidyl peptidase-4 (DPP-4) and integrin β1 have shown to be involved in EMT program. Here, we found diabetic kidney is prone for albuminuria-induced TECs damage and DPP-4 plays a vital role in such parenchymal damages in diabetic mice. The bovine serum albumin (BSA) injection induced severe TECs damage and altered expression levels of DPP-4, integrin β1, CAV1, and EMT programs including relevant microRNAs in type 1 diabetic CD-1 mice when compared to non-diabetic mice; teneligliptin (TENE) ameliorated these alterations. TENE suppressed the close proximity among DPP-4, integrin β1 and CAV1 in a culture of HK-2 cells. These findings suggest that DPP-4 inhibition can be relevant for combating proteinuric DKD by targeting the EMT program induced by the crosstalk among DPP-4, integrin β1 and CAV1.
糖尿病肾病（DKD）与白蛋白尿程度相同的非糖尿病肾病相比，肾功能下降的风险似乎更高。肾小管上皮细胞（TEC）的上皮-间充质转化（EMT）程序可能对肾脏细胞外基质的产生很重要。窖蛋白-1（CAV1）、二肽基肽酶-4（DPP-4）和整合素β1 已被证明参与 EMT 程序。在这里，我们发现糖尿病肾脏容易发生白蛋白尿诱导的 TEC 损伤，而 DPP-4 在糖尿病小鼠的这种实质损伤中起着至关重要的作用。与非糖尿病小鼠相比，牛血清白蛋白（BSA）注射诱导 1 型糖尿病 CD-1 小鼠的严重 TEC 损伤，并改变了 DPP-4、整合素β1、CAV1 的表达水平以及 EMT 程序，包括相关 microRNAs；替奈利汀（TENE）改善了这些变化。TENE 在 HK-2 细胞的培养中抑制了 DPP-4、整合素β1 和 CAV1 之间的紧密接近。这些发现表明，通过靶向 DPP-4、整合素β1 和 CAV1 之间的串扰诱导的 EMT 程序，抑制 DPP-4 可能与对抗蛋白尿性 DKD 有关。
