Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea.
Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea.
Korean J Intern Med. 2021 Jul;36(4):962-974. doi: 10.3904/kjim.2020.198. Epub 2020 Dec 16.
BACKGROUND/AIMS: Acute kidney injury (AKI) is an underestimated yet important risk factor for the development of chronic kidney disease (CKD), characterized by tubulointerstitial fibrosis and tubular dedifferentiation. Tubular dedifferentiation, which is associated with the loss of epithelial markers and the gain of mesenchymal features, is thought to be involved in tubulointerstitial fibrosis. As protein kinase B/Akt is involved in the development of CKD, we investigated the role of Akt1, one of the three Akt isoforms, in a murine model of AKI-to-CKD progression.
We subjected C57BL/6 male mice to unilateral ischemia-reperfusion injury (UIRI) and harvested their kidneys after 6 weeks. Mice were divided into four groups, namely, wild-type (WT) UIRI, Akt1-/- UIRI, WT sham, and Akt1-/- sham.
Akt1 (but not Akt2 or Akt3) was markedly activated in WT UIRI mice than in WT sham mice. Tubulointerstitial fibrosis and tubular dedifferentiation significantly increased in WT UIRI mice, but were attenuated in Akt1-/- UIRI mice. Both WT UIRI and Akt1-/- UIRI mice showed markedly upregulated transforming growth factor-β1 (TGF-β1)/Smad signaling compared with WT sham mice. However, TGF-β1/Smad expression did not differ between the two groups. The levels of phosphorylated GSK-3β, β-catenin, and Snail were attenuated in Akt1-/- UIRI mice compared with those in WT UIRI mice.
Deletion of Akt1 results in the attenuation of renal fibrosis and tubular dedifferentiation, independent of TGF-β1/Smad signaling, during AKI-to-CKD progression in a UIRI without contralateral nephrectomy model. Thus, Akt1 may serve as a therapeutic target in AKI-to-CKD progression.
背景/目的：急性肾损伤（AKI）是慢性肾脏病（CKD）发展的一个被低估但很重要的危险因素，其特征为肾小管间质性纤维化和肾小管去分化。肾小管去分化与上皮标志物的丢失和间质特征的获得有关，被认为与肾小管间质性纤维化有关。由于蛋白激酶 B/Akt 参与 CKD 的发生发展，我们研究了 Akt1（Akt 的三个同工型之一）在 AKI 向 CKD 进展的小鼠模型中的作用。
我们使 C57BL/6 雄性小鼠单侧缺血再灌注损伤（UIRI），并在 6 周后采集其肾脏。将小鼠分为四组，即野生型（WT）UIRI、Akt1-/-UIRI、WT 假手术和 Akt1-/-假手术。
与 WT 假手术组相比，WT UIRI 小鼠的 Akt1（而非 Akt2 或 Akt3）明显被激活。WT UIRI 小鼠的肾小管间质性纤维化和肾小管去分化明显增加，但在 Akt1-/-UIRI 小鼠中被减弱。与 WT 假手术组相比，WT UIRI 和 Akt1-/-UIRI 小鼠的转化生长因子-β1（TGF-β1）/Smad 信号均明显上调。然而，两组间 TGF-β1/Smad 表达无差异。与 WT UIRI 组相比，Akt1-/-UIRI 组的磷酸化 GSK-3β、β-连环蛋白和 Snail 水平降低。
在未进行对侧肾切除术的 UIRI 模型中，Akt1 的缺失导致 AKI 向 CKD 进展过程中肾脏纤维化和肾小管去分化的减弱，与 TGF-β1/Smad 信号无关。因此，Akt1 可能是 AKI 向 CKD 进展的治疗靶点。
