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Abstract: FR-PO1007

Intrinsic TGF-β Signaling in Proximal Tubule Metabolism and Response to Chronic Injury

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

  • Kayhan, Merve, Universitat Zurich, Zurich, ZH, Switzerland
  • Vouillamoz, Judith, Universitat Zurich, Zurich, ZH, Switzerland
  • Bugarski, Milica, Universitat Zurich, Zurich, ZH, Switzerland
  • Hall, Andrew, Universitat Zurich, Zurich, ZH, Switzerland
  • Gewin, Leslie S., Washington University in St Louis, St Louis, Missouri, United States
  • Wenger, Roland H., Universitat Zurich, Zurich, ZH, Switzerland
  • Nlandu khodo, Stellor, Universitat Zurich, Zurich, ZH, Switzerland
Background

The proximal tubule (PT) is the most metabolic and pivotal renal segment in the pathogenesis of chronic kidney disease (CKD). Excessive TGF-β signaling and mitochondria dysfunction are two features of CKD, however, how intrinsic TGF-β signaling and mitochondria interplay in PT response to chronic injury is unknown. We recently reported the beneficial effect of intact TGF-β signaling in PT response to chronic injury; our RNAseq analysis revealed mitochondria as the most affected cellular component in PT cells lacking the TGF-β receptor (TβRII). We therefore hypothesized that intrinsic TGF-β signaling is crucial for PT mitochondrial integrity and response to chronic injury.

Methods

To test this, mice lacking TβRII in the PT (γGT-Cre;Tgfbr2fl/fl) and their floxed littermates were injured using aristolochic acid (AA) model of CKD, and PT mitochondria and renal outcomes were analyzed.

Results

Electron and multiphoton intravital microscopy showed severe mitochondrial injury and dysfunction in AA-injured γGT-Cre;Tgfbr2fl/fl mice as compared to their floxed littermates. FACS analysis showed increased adaptive immune response, especially the Cgas/Sting/IFNγ axis in gGT-Cre;Tgfbr2fl/fl mice. Consistently, 10X spatial transcriptomics confirmed increased cortical injury and fibrosis, and decreased renal function (BUN) in γGT-Cre;Tgfbr2fl/fl mice. Further analysis revealed impaired expression of electron transport chain (ETC) proteins (Complex I), mitochondrial biogenesis and mitophagy (mito-QC reporter mice) associated with oxidative stress and a metabolic rewiring towards aerobic glycolysis (Seahorse) in the absence of TβRII. Treatment of PT cells with NAD+ increased ATP production and reduced oxidative stress in PT cells lacking TβRII.

Conclusion

This study points out the role of TGF-β signaling in maintaining PT metabolism partly by controlling ETC proteins expression, mitochondrial biogenesis and mitophagy, and how this role affects PT response to CKD.

Funding

  • Government Support – Non-U.S.