Calponin 2 regulates ketogenesis to dictate the outcome of acute kidney injury
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 functions, mitigated tubular cell death and inflammation, and promoted cell proliferation. Distinct from kidney fibrosis, proteomics showed that the key elements in the FAO pathway have little changes in AKI, but we identified that 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 ketone bodies ß-hydroxybutyrate and ATP production were increased in CNN2 knockdown mice. Mechanistically, CNN2 interacts with ESR2 to activate mitochonrial sirtuin 5, subsequently desuccinylating HMGCS2 to produce energy for AKI repair. Understanding CNN2-mediated discrete fine-tuning of protein posttranslational modification is critical to optimize organ performance after AKI. Overall design: RNA-seq data on mouse kidney after acute kidney injury at different time points