Calponin 2 harnesses metabolic reprogramming to determine kidney fibrosis

Yuan Gui; Yuanyuan Wang; Zachary Palanza; Jack L Wang; Priya Gupta; Jianling Tao; Yi Qiao; Geneva Hargis; Donald L Kreutzer; Sheldon I Bastacky; Yanbao Yu; Yanlin Wang; Silvia Liu; Haiyan Fu; Dong Zhou

doi:10.1016/j.molmet.2023.101712

Calponin 2 harnesses metabolic reprogramming to determine kidney fibrosis

Mol Metab. 2023 May:71:101712. doi: 10.1016/j.molmet.2023.101712. Epub 2023 Mar 22.

Authors

Yuan Gui¹, Yuanyuan Wang¹, Zachary Palanza¹, Jack L Wang¹, Priya Gupta¹, Jianling Tao², Yi Qiao³, Geneva Hargis⁴, Donald L Kreutzer³, Sheldon I Bastacky⁵, Yanbao Yu⁶, Yanlin Wang¹, Silvia Liu⁵, Haiyan Fu⁷, Dong Zhou⁸

Affiliations

¹ Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, 06030, USA.
² Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
³ Department of Surgery, University of Connecticut School of Medicine, Farmington, CT, 06030, USA.
⁴ University of Connecticut, School of Medicine, Farmington, CT, 06030, USA.
⁵ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
⁶ Department of Chemistry & Biochemistry, University of Delaware, Newark, DE, 19716, USA.
⁷ State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
⁸ Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, 06030, USA. Electronic address: dzhou@uchc.edu.

Abstract

Objective: 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. In mice, 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 the 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.

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

Keywords: Calponin 2; Chronic kidney disease; ESR2; Fatty acid oxidation; Proteomics.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Calmodulin-Binding Proteins* / metabolism
Calponins
Fibrosis
Kidney / metabolism
Kidney / pathology
Kidney Diseases* / metabolism
Kidney Diseases* / pathology
Mice
PPAR alpha / metabolism

Substances

PPAR alpha
Cnn2 protein, mouse
Calmodulin-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding