Empagliflozin protected kidney function in CKD rat through suppressing hypoxic and fibrotic signalings mediated inflammation and EMT

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Yang-41-319-337-2026.pdf(37.49 MB)
Date
2026
Authors
Jui-Ning Yeh
Tsuen-Wei Hsu
John Y. Chiang
Ben-Chung Cheng
Pei-Hsun Sung
Shun-Cheng
Chi-Ruei Huang
Pei-Lin Shao
Hon-Kan Yip
Chih-Chao Yang
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Volume Title
Publisher
Universidad de Murcia, Departamento de Biologia Celular e Histiologia
Abstract
Background. This study tested the hypothesis that PI3K/Akt/GSK3β and TGF-β/Smad2/3 signaling play essential roles in mediating the epithelial-mesenchymal transition (EMT) and fibrosis, resulting in the deterioration of renal function and parenchyma in chronic kidney disease (CKD) rats, which is reversed by early empagliflozin treatment. Methods and results. NRK-52E cells were divided into the A1 (NRK-52E), A2 (NRK-52E + 200 μM p-Cresol), A3 (NRK-52E + 200 μM p-Cresol + 50 μM empagliflozin), B1 (NRK-52E), B2 (NRK-52E + 5 ng/mL TGF-β1) and B3 (NRK-52E + 5 ng/mL TGF-β1 + 50 μM empagliflozin) groups. Compared with those in the A1 group, the expression levels of proteins related to the EMT (TGF-β1/p-Smad2/p-Smad3/α-SMA), extracellular matrix (MMP2/9) and EMT (IGF-1) activators were significantly higher in the A2 group, but these changes were significantly reversed in the A3 group, whereas the protein expression levels of antifibrotic markers (TIMP1/TIMP2) exhibited the opposite pattern to the EMT-related proteins among the groups (all p<0.001). The expression of these proteins, along with the other EMT markers (snail, fibronectin, and vimentin) related to cellular function/protein expression, also exhibited an identical pattern to the A1 to A3 groups among Groups B1 to B3 (all p<0.001). Adult male SD rats were categorized into Groups 1 (sham-operated control), 2 (CKD) and 3 (CKD + empagliflozin). On Day 56 after CKD induction, the renal artery resistive index (RARI) was significantly higher in Group 2 than in Groups 1 and 3 and significantly higher in Group 3 than in Group 1 (all p<0.0001). The expression of EMT (Snail/α-SMA/ fibronectin/vimentin/TGF-β1/p-Smad2/3), apoptotic (cleaved caspase-3/cleaved-PARP), inflammatory (HIF-1α/IL-1β/TNF-α/MPO/MMP-2/MMP-9), and cell stress signaling (p-PI3K/p-Akt/GSK-3β) proteins and the cellular kidney injury score, expression of fibrosis and EMT markers (Snail/vimentin)/glomerular-hyper-cellularity/fibrocellular crescent formation displayed an identical pattern, whereas the cellular expression of podocyte components (podocin/synaptopodin/ZO-1) displayed the opposite pattern to the RARIs among the groups (all p<0.0001). Conclusions. Empagliflozin protected kidney function and architecture mainly by suppressing fibrosis, cellular oxidative stress signaling, the EMT and inflammation.
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Keywords
Epithelial-mesenchymal transition , Inflammation , Cell stress/ fibrosis signaling , SGLT-2 inhibitor , Chronic kidney disease
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http://hdl.handle.net/10201/184590
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Histology and histopathology, Vol.41, Nº2, (2026)
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