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Updated: Jul 12, 2026
06:40
Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
Published on: February 9, 2014
C5a/C5aR1 mediates AKI-CKD transition by enhancing autophagy.
Jingyuan Ma1, Wai Han Yiu1, Sarah W Y Lok1
1Division of Nephrology, Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Summary
The C5a/C5aR1 axis in kidney tubular cells drives chronic kidney disease progression by promoting inflammation and disrupting mitochondrial function. Targeting C5aR1 may prevent chronic kidney disease development.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Elevated complement C5a is observed in acute kidney injury (AKI) and chronic kidney disease (CKD), suggesting a role in CKD progression.
- The precise mechanisms by which C5a influences CKD progression remain incompletely understood.
Purpose of the Study:
- To elucidate the role of the C5a/C5aR1 axis in the transition from AKI to CKD.
- To investigate the cellular mechanisms underlying C5a-mediated kidney damage and fibrosis.
Main Methods:
- Utilized global, tubule-specific, and myeloid-specific C5aR1 knockout mice subjected to bilateral ischemia reperfusion injury (BIRI).
- Employed PMX53, a C5aR1 antagonist, in mouse models and in vitro studies.
- Investigated cellular mechanisms using cultured kidney tubular epithelial cells and bone marrow-derived macrophages.
Main Results:
- Tubule-specific C5aR1 deficiency attenuated pro-inflammatory responses, oxidative stress, and tubulointerstitial fibrosis by promoting M2 macrophage polarization.
- Deletion of tubular C5aR1 enhanced mitochondrial biogenesis, increased ATP production, and reduced apoptosis via autophagy induction.
- In vitro, PMX53 treatment reduced apoptosis in kidney tubular cells by enhancing BNIP3-regulated autophagy, modulating macrophage polarization and inflammation.
Conclusions:
- The C5a/C5aR1 axis detrimentally impacts AKI-to-CKD transition by polarizing macrophages towards a chronic inflammatory phenotype and impairing mitochondrial homeostasis through BNIP3-regulated autophagy.
- These effects lead to tubulointerstitial fibrosis and kidney dysfunction.
- Targeting C5aR1 presents a potential therapeutic strategy for preventing CKD progression.
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