Related Experiment Video
Updated: Jul 15, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Calponin 2 regulates ketogenesis to mitigate acute kidney injury
Yuan Gui1, Zachary Palanza1, Priya Gupta1
1Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA.
Abstract:
Calponin 2 (CNN2) is a prominent actin stabilizer. It regulates fatty acid oxidation (FAO) by interacting with estrogen receptor 2 (ESR2) to determine kidney fibrosis. However, whether CNN2 is actively involved in acute kidney injury (AKI) remains unclear. Here, we report that CNN2 was induced in human and animal kidneys after AKI. Knockdown of CNN2 preserved kidney function, mitigated tubular cell death and inflammation, and promoted cell proliferation. Distinct from kidney fibrosis, proteomics showed that the key elements in the FAO pathway had few changes during AKI, but we identified that 3-hydroxymethylglutaryl-CoA synthase 2 (Hmgcs2), a rate-limiting enzyme of endogenous ketogenesis that promotes cell self-renewal, was markedly increased in CNN2-knockdown kidneys. The production of ketone body β-hydroxybutyrate and ATP was increased in CNN2-knockdown mice. Mechanistically, CNN2 interacted with ESR2 to negatively regulate the activities of mitochondrial sirtuin 5. Activated sirtuin 5 subsequently desuccinylated Hmgcs2 to produce energy for mitigating AKI. Understanding CNN2-mediated discrete fine-tuning of protein posttranslational modification is critical to optimize organ performance after AKI.
Insights
Calponin 2 (CNN2) plays a key role in acute kidney injury (AKI). Reducing CNN2 levels protected kidney function and promoted self-renewal by enhancing ketogenesis and ATP production.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Calponin 2 (CNN2) stabilizes actin and influences fatty acid oxidation (FAO) via estrogen receptor 2 (ESR2), impacting kidney fibrosis.
- The role of CNN2 in acute kidney injury (AKI) has not been previously established.
Purpose of the Study:
- To investigate the role of CNN2 in the development and progression of AKI.
- To elucidate the underlying molecular mechanisms of CNN2's involvement in AKI.
Main Methods:
- Analysis of CNN2 expression in human and animal AKI models.
- Gene knockdown experiments to assess CNN2's functional impact on kidney injury.
- Proteomic analysis to identify key molecular pathways affected by CNN2.
- Investigation of protein-protein interactions and posttranslational modifications.
Main Results:
- CNN2 expression was upregulated in kidneys following AKI.
- Knockdown of CNN2 ameliorated kidney dysfunction, reduced tubular cell death and inflammation, and enhanced cell proliferation.
- CNN2-knockdown kidneys showed increased 3-hydroxymethylglutaryl-CoA synthase 2 (Hmgcs2) expression, leading to elevated ketone body and ATP production.
- CNN2 was found to interact with ESR2, negatively regulating mitochondrial sirtuin 5 activity, which in turn desuccinylates Hmgcs2.
Conclusions:
- CNN2 is actively involved in AKI pathogenesis.
- Targeting CNN2 may offer a therapeutic strategy for mitigating AKI by modulating ketogenesis and cellular energy metabolism.
- Understanding CNN2's regulation of protein posttranslational modifications is crucial for optimizing kidney recovery after AKI.
Related Concept Videos
01:29Acute Kidney Injury II: Pathophysiology
01:22Acute Kidney Injury I: Introduction
01:20Acute Kidney Injury V: Interprofessional Care
01:29Acute Kidney Injury III: Clinical Manifestations
01:30Acute Kidney Injury IV: Diagnostic Studies and Prevention
01:29Renal Regulation of Acid-Base Balance
In the kidneys, cells within the proximal convoluted tubules (PCT) and the collecting ducts secrete hydrogen ions (H+) into the tubular fluid. Specifically, in the PCT, Na+/H+ antiporters secrete H+ while reabsorbing Na+.
However, the intercalated cells in...