FoxO1-Mediated Inhibition of STAT1 Alleviates Tubulointerstitial Fibrosis and Tubule Apoptosis in Diabetic Kidney Disease
46 Pages Posted: 2 Aug 2019More...
Background: Tubulointerstitial fibrosis (TIF) plays an important role in the progression of diabetic kidney disease (DKD). Forkhead box O1 (FoxO1) is involved in the regulation of metabolism and cell apoptosis, but its function in renal TIF induced by DKD is less well understood.
Methods: Both in vitro and in vivo assays were performed to investigate the roles of FoxO1 in TIF induced by diabetes. A mouse model with kidney-specific overexpression of Pax2-3aFoxO1 was used to investigate the functions of FoxO1 in vivo. The in vitro functions of FoxO1 were analyzed in HK-2 cells with 3aFoxO1-knockin (3aFoxO1-KI) or FoxO1-knockdown (FoxO1-KD) via CRISPR/Cas9. Western blot, immunohistochemistry and chromatin immunoprecipitation were used to explore the underlying mechanisms.
Findings: In vivo study showed that kidney-specific overexpression of Pax2-3aFoxO1 significantly reduced the expression of STAT1 with resultant renal functional impairment, retarding renal TIF and apoptosis in diabetic mice. Meanwhile, We observed that FoxO1-KD in HK-2 cells aggravated the expression of STAT1, leading to activation of epithelial-to-mesenchymal transition (EMT) and intrinsic apoptotic pathway. Conversely, EMT and apoptosis were significantly attenuated in HK-2 cells with 3aFoxO1-KI under hyperglycemic conditions.
Interpretation: Taken together, these data suggest that the protection role of FoxO1 against renal TIF and apoptosis in DKD is likely in part to target STAT1 signaling, which may be a promising strategy for long-term treatment of DKD.
Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (grant numbers: 81570746 and 81770812).
Declaration of Interests: The authors declare no competing financial interests.
Ethics Approval Statement: The Ethics Committee from Zhengzhou University approved the use of patient tissue samples in this study. All procedures conducted in accordance with the Principles of Laboratory Animal Care, and were approved by the institutional committees of the Animal Research Committee and Animal Ethics Committee of Zhengzhou University.
Keywords: FoxO1; STAT1; apoptosis; diabetic kidney disease; tubulointerstitial fibrosis
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