Korean J Intern Med.  2021 Jul;36(4):962-974. 10.3904/kjim.2020.198.

Role of Akt1 in renal fibrosis and tubular dedifferentiation during the progression of acute kidney injury to chronic kidney disease

• Kim IY
• Park YK
• Song SH
• Seong EY
• Lee DW
• Bae SS
• Lee SB

• KMID: 2517813
• DOI: http://doi.org/10.3904/kjim.2020.198

Abstract

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.
Methods
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.
Results
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.
Conclusions
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.

Keyword

Acute kidney injury; Akt1; Chronic kidney disease; Tubular dedifferentiation; Renal fibrosis