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Lu, YongPing [Author]; Wu, Hong-Wei [Author]; Zhu, Ting [Author]; Li, Xi-Tong [Author]; Zuo, Jiao [Author]; Hasan, Ahmed A. [Author]; Reichetzeder, Christoph [Author]; Delic, Denis [Author]; Yard, Benito A. [Author]; Klein, Thomas [Author]; Krämer, Bernhard [Author]; Zhang, Ze-Yu [Author]; Wang, Xiao-Hua [Author]; Yin, Liang-Hong [Author]; Dai, Yong [Author]; Zheng, Zhi-Hua [Author]; Hocher, Berthold [Author]

Empagliflozin reduces kidney fibrosis and improves kidney function by alternative macrophage activation in rats with 5/6-nephrectomy

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  • Media type: E-Article
  • Title: Empagliflozin reduces kidney fibrosis and improves kidney function by alternative macrophage activation in rats with 5/6-nephrectomy
  • Contributor: Lu, YongPing [VerfasserIn]; Wu, Hong-Wei [VerfasserIn]; Zhu, Ting [VerfasserIn]; Li, Xi-Tong [VerfasserIn]; Zuo, Jiao [VerfasserIn]; Hasan, Ahmed A. [VerfasserIn]; Reichetzeder, Christoph [VerfasserIn]; Delic, Denis [VerfasserIn]; Yard, Benito A. [VerfasserIn]; Klein, Thomas [VerfasserIn]; Krämer, Bernhard [VerfasserIn]; Zhang, Ze-Yu [VerfasserIn]; Wang, Xiao-Hua [VerfasserIn]; Yin, Liang-Hong [VerfasserIn]; Dai, Yong [VerfasserIn]; Zheng, Zhi-Hua [VerfasserIn]; Hocher, Berthold [VerfasserIn]
  • imprint: 31 October 2022
  • Published in: Biomedicine & pharmacotherapy ; 156(2022) vom: Dez., Artikel-ID 113947, Seite 1-11
  • Language: English
  • DOI: 10.1016/j.biopha.2022.113947
  • ISSN: 1950-6007
  • Identifier:
  • Keywords: Fibrosis ; Macrophage-myofibroblast transition ; Non-diabetic kidney disease ; Polarization ; SGLT2 inhibitor
  • Origination:
  • Footnote: Online verfügbar: 31 October 2022, Artikelversion: 31 October 2022
  • Description: 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.
  • Access State: Open Access