Empagliflozin reduces kidney fibrosis and improves kidney function by alternative macrophage activation in rats with 5/6-nephrectomy
Background - Sodium glucose cotransporter 2 (SGLT2) inhibitors originally developed for the treatment of type 2 diabetes are clinically very effective drugs halting chronic kidney disease progression. The underlying mechanisms are, however, not fully understood. - Methods - We generated single-cell...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
31 October 2022
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| In: |
Biomedicine & pharmacotherapy
Year: 2022, Volume: 156, Pages: 1-11 |
| ISSN: | 1950-6007 |
| DOI: | 10.1016/j.biopha.2022.113947 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.biopha.2022.113947 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S0753332222013361 
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| Author Notes: | Yong-Ping Lu, Hong-Wei Wu, Ting Zhu, Xi-Tong Li, Jiao Zuo, Ahmed A. Hasan, Christoph Reichetzeder, Denis Delic, Benito Yard, Thomas Klein, Bernhard K. Krämer, Ze-Yu Zhang, Xiao-Hua Wang, Liang-Hong Yin, Yong Dai, Zhi-Hua Zheng, Berthold Hocher |
| Summary: | Background - Sodium glucose cotransporter 2 (SGLT2) inhibitors originally developed for the treatment of type 2 diabetes are clinically very effective drugs halting chronic kidney disease progression. The underlying mechanisms are, however, not fully understood. - Methods - We generated single-cell transcriptomes of kidneys from rats with 5/6 nephrectomy before and after SGLT2 inhibitors treatment by single-cell RNA sequencing. - Findings - Empagliflozin treatment decreased BUN, creatinine and urinary albumin excretion compared to placebo by 39.8%, 34.1%, and 55%, respectively (p < 0.01 in all cases). Renal interstitial fibrosis and glomerulosclerosis was likewise decreased by 51% and 66.8%; respectively (p < 0.05 in all cases). 14 distinct kidney cell clusters could be identified by scRNA-seq. The polarization of M2 macrophages from state 1 (CD206-CD68- M2 macrophages) to state 5 (CD206+CD68+ M2 macrophages) was the main pro-fibrotic process, as CD206+CD68+ M2 macrophages highly expressed fibrosis-promoting genes and can convert into fibrocytes. Empagliflozin remarkably inhibited the expression of fibrosis-promoting (IFG1 and TREM2) and polarization-associated genes (GPNMB, LGALS3, PRDX5, and CTSB) in CD206+CD68+ M2 macrophages and attenuated inflammatory signals from CD8+ effector T cells. The inhibitory effect of empagliflozin on CD206+CD68+ M2 macrophages polarization was mainly achieved by affecting mitophagy and mTOR pathways. - Interpretation - We propose that the beneficial effects of empagliflozin on kidney function and morphology in 5/6 nephrectomyiced rats with established CKD are at least partially due to an inhibition of CD206+CD68+ M2 macrophage polarization by targeting mTOR and mitophagy pathways and attenuating inflammatory signals from CD8+ effector T cells. - Fundings - A full list of funding bodies that contributed to this study can be found in the Acknowledgements section. |
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| Item Description: | Online verfügbar: 31 October 2022, Artikelversion: 31 October 2022 Gesehen am 20.06.2023 |
| Physical Description: | Online Resource |
| ISSN: | 1950-6007 |
| DOI: | 10.1016/j.biopha.2022.113947 |