Calponin 2 harnesses metabolic reprogramming to determine kidney fibrosis

Elsevier

Available online 22 March 2023, 101712

Molecular MetabolismAuthor links open overlay panel, , , , , , , , , , , , , , Highlights•

Serum CNN2 was increased in CKD patients.

Knockdown of CNN2 alleviated kidney fibrosis in CKD models.

Knockdown of CNN2 enhanced FAO and reduced lipid accumulation after CKD.

Knockdown of CNN2 preserved kidney functions once CPT-1α was inhibited.

CNN2 interacts with ESR2 to transcriptionally modulate the activity of PPARα.

AbstractObjective

In the fibrotic kidneys, the extent of a formed deleterious microenvironment is determined by cellular mechanical forces. This process requires metabolism for energy. However, how cellular mechanics and metabolism are connected remains unclear.

Methods

A multi-disciplinary approach was employed: the fibrotic kidney disease models were induced by renal ischemia-reperfusion injury and unilateral ureteral obstruction in Calponin 2 (CNN2) knockdown mice. Proteomics, bioinformatics, and in vivo and in vitro molecular experimental pathology studies were performed.

Result

Our proteomics revealed that actin filament binding and cell metabolism are the two most dysregulated events in the fibrotic kidneys. As a prominent actin stabilizer, CNN2 was predominantly expressed in fibroblasts and pericytes. In CKD patients, CNN2 levels was markedly induced in blood. CNN2 knockdown preserves kidney function and alleviates fibrosis. Global proteomics profiled that CNN2 knockdown enhanced the activities of the key rate-limiting enzymes and regulators of fatty acid oxidation (FAO) in diseased kidneys. Inhibiting carnitine palmitoyltransferase 1α in the FAO pathway resulted in lipid accumulation and extracellular matrix deposition in the fibrotic kidneys, which were restored after CNN2 knockdown. Bioinformatics and chromatin immunoprecipitation showed that CNN2 interactor, estrogen receptor 2 (ESR2), binds peroxisome proliferator-activated receptor-α (PPARα) to transcriptionally regulate FAO downstream target genes expression amid kidney fibrosis. In vitro, ESR2 knockdown repressed the mRNA levels of PPARα and the key genes in the FAO pathway. Conversely, activation of PPARα reduced CNN2-induced matrix inductions.

Conclusion

Our results suggest that balancing cell mechanics and metabolism is crucial to develop therapeutic strategies to halt kidney fibrosis.

Keywords

Calponin 2

ESR2

fatty acid oxidation

proteomics

chronic kidney disease

© 2023 The Author(s). Published by Elsevier GmbH.

留言 (0)

沒有登入
gif