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Kidney Week

Abstract: FR-PO956

Empagliflozin Reduces Kidney Fibrosis and Improves Kidney Function by Alternative Macrophage Activation in Rats With 5/6-Nephrectomy

Session Information

  • CKD: Pathobiology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Wu, Hongwei, Universitatsklinikum Mannheim, Mannheim, Baden-Württemberg, Germany
  • Hocher, Berthold, Universitatsklinikum Mannheim, Mannheim, Baden-Württemberg, Germany
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.

Results

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 were 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 the mTOR-mitophagy pathway.

Conclusion

The beneficial effects of empagliflozin on kidney function and morphology in 5/6 nephrectomized 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.

The mechanism map for CD206+CD68+ M2 macrophages polarization and the target effects of empagliflozin on kidney fibrosis

Funding

  • Private Foundation Support