Intrinsic TGF-β signaling attenuates proximal tubule mitochondrial injury and inflammation in chronic kidney disease

Merve Kayhan, Judith Vouillamoz, Daymé Gonzalez Rodriguez, Milica Bugarski, Yasutaka Mitamura, Julia Gschwend, Christoph Schneider, Andrew Hall, David Legouis, Cezmi A. Akdis, Leary Peter, Hubert Rehrauer, Leslie Gewin, Roland H. Wenger and Stellor Nlandu Khodo ()
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Merve Kayhan: University of Zurich
Judith Vouillamoz: University of Zurich
Daymé Gonzalez Rodriguez: University of Zurich and ETH Zurich
Milica Bugarski: University of Zurich
Yasutaka Mitamura: University of Zurich
Julia Gschwend: University of Zurich
Christoph Schneider: University of Zurich
Andrew Hall: University of Zurich
David Legouis: Hospital and University of Geneva
Cezmi A. Akdis: University of Zurich
Leary Peter: University of Zurich and ETH Zurich
Hubert Rehrauer: University of Zurich and ETH Zurich
Leslie Gewin: Washington University
Roland H. Wenger: University of Zurich
Stellor Nlandu Khodo: University of Zurich

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Excessive TGF-β signaling and mitochondrial dysfunction fuel chronic kidney disease (CKD) progression. However, inhibiting TGF-β failed to impede CKD in humans. The proximal tubule (PT), the most vulnerable renal segment, is packed with giant mitochondria and injured PT is pivotal in CKD progression. How TGF-β signaling affects PT mitochondria in CKD remained unknown. Here, we combine spatial transcriptomics and bulk RNAseq with biochemical analyses to depict the role of TGF-β signaling on PT mitochondrial homeostasis and tubulo-interstitial interactions in CKD. Male mice carrying specific deletion of Tgfbr2 in the PT have increased mitochondrial injury and exacerbated Th1 immune response in the aristolochic acid model of CKD, partly, through impaired complex I expression and mitochondrial quality control associated with a metabolic rewiring toward aerobic glycolysis in the PT cells. Injured S3T2 PT cells are identified as the main mediators of the maladaptive macrophage/dendritic cell activation in the absence of Tgfbr2. snRNAseq database analyses confirm decreased TGF-β receptors and a metabolic deregulation in the PT of CKD patients. This study describes the role of TGF-β signaling in PT mitochondrial homeostasis and inflammation in CKD, suggesting potential therapeutic targets that might be used to mitigate CKD progression.

Date: 2023
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DOI: 10.1038/s41467-023-39050-y

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