Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 14.
doi: 10.1007/s40618-025-02650-0. Online ahead of print.

Dapagliflozin ameliorates high glucose-induced epithelial-mesenchymal transition via up-regulating ACE2 mediated by EZH2 in diabetic nephropathy

Simeng Wang  1   2 , Xinyu Zhang  1 , Nannan Chong  3 , Dandan Chen  1 , Jianqiang Shu  1 , Rong Wang  4 , Qinglian Wang  4 , Ying Xu  5
Affiliations

Dapagliflozin ameliorates high glucose-induced epithelial-mesenchymal transition via up-regulating ACE2 mediated by EZH2 in diabetic nephropathy

Simeng Wang et al. J Endocrinol Invest. .

Abstract

Purpose: To investigate the protective function and underlying mechanism of dapagliflozin on tubulointerstitial fibrosis (TIF) in diabetic nephropathy (DN).

Methods: In this study, we constructed the high-fat and high-glucose diet combined with streptozocin (STZ)-induced DN rat model and 0.2 mg/kg/d of dapagliflozin pretreatment model. After the experiment, kidney tissues were retained for subsequent experiments. In vitro, human renal tubular epithelial cells were treated with different concentrations of glucose and dapagliflozin to investigate the reno-protective functions and potential mechanisms of dapagliflozin in DN.

Results: Our study revealed that dapagliflozin could significantly inhibit epithelial-mesenchymal transition (EMT) and TIF. Meanwhile, dapagliflozin improved cytoskeleton rearrangement and cellular migration capacity. Also, dapagliflozin restored the expression of angiotensin-converting enzyme 2 (ACE2) in human proximal tubular epithelial cells (HK2) and DN rats. Rescue experiments additionally demonstrated that the effects of dapagliflozin were attenuated by blocking ACE2 with MLN-4760, an ACE2 inhibitor, and by siRNA knockdown of ACE2 in HK2 cells. In addition, MLN-4760 and si-ACE2 reversed the decreased pro-fibrotic cytokine TGF-β1 induced by dapagliflozin. Further, results showed that dapagliflozin could inhibit EZH2 and H3K27me3 expression. H3K27me3 partially co-localized with ACE2 and their expression was negatively correlated. Following the over-expression of EZH2, there was a significant up-regulation of H3K27me3 in HK2 cells, then the high expression of ACE2 induced by dapagliflozin was significantly inhibited.

Conclusions: Dapagliflozin could up-regulate ACE2 by inhibiting EZH2-mediated ACE2 histone methylation, further exerting anti-fibrotic effects by inhibiting downstream activation of TGF-β1.

Keywords: ACE2; Dapagliflozin; Diabetic nephropathy; EZH2; Histone methylation.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study involving animals met the Animals in Research Reporting In Vivo Experiments (ARRIVE) guidelines and followed the guidelines of the National Institutes of Health guide. All experiments were approved by the hospital ethics committees of Shandong Provincial Hospital Affiliated to Shandong First Medical University (No. 2020-070). Consent for publication: Consent for publication was obtained from all the listed authors. Completing interests: The authors report there are no competing interests to declare. Research involving human participants: This article does not contain any studies with human participants performed by any of the authors. Informed consent: For this type of study informed consent is not required.

Similar articles

See all similar articles

References

    1. Selby NM, Taal MW (2020) An updated overview of diabetic nephropathy: diagnosis, prognosis, treatment goals and latest guidelines. DIABETES OBES METAB 22(Suppl 1):3–15 - PubMed
    1. Zeng LF, Xiao Y, Sun L (2019) A glimpse of the mechanisms related to renal fibrosis in diabetic nephropathy. ADV EXP MED BIOL 1165:49–79 - PubMed
    1. Yan Q, Zhu K, Zhang L et al (2020) A negative feedback loop between JNK-associated leucine zipper protein and TGF-beta1 regulates kidney fibrosis. COMMUN BIOL 3:288 - PubMed - PMC
    1. Cruz-Solbes AS, Youker K (2017) Epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (EndMT): role and implications in kidney fibrosis. Results Probl Cell Differ 60:345–372 - PubMed
    1. Sagoo MK, Gnudi L (2020) Diabetic nephropathy: an overview. Methods Mol Biol 2067:3–7 - PubMed

LinkOut - more resources