Calponin 2 regulates ketogenesis to mitigate acute kidney injury

被引：5

作者：

Gui, Yuan ^{[1
]}

Palanza, Zachary ^{[1
]}

Gupta, Priya ^{[1
]}

Li, Hanwen ^{[2
]}

Pan, Yuchen ^{[3
]}

Wang, Yuanyuan ^{[1
]}

Hargis, Geneva ^{[4
]}

Kreutzer, Donald L. ^{[5
]}

Wang, Yanlin ^{[1
]}

Bastacky, Sheldon I. ^{[6
]}

Liu, Yansheng ^{[7
,8
]}

Liu, Silvia ^{[6
]}

Zhou, Dong ^{[1
,9
]}

机构：

[1] Univ Connecticut, Sch Med, Dept Med, Div Nephrol, Farmington, CT USA

[2] Univ Pittsburgh, Kenneth P Dietrich Sch Arts & Sci, Dept Stat, Pittsburgh, PA USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX USA

[4] Univ Connecticut, Sch Med, Farmington, CT USA

[5] Univ Connecticut, Sch Med, Dept Surg, Farmington, CT USA

[6] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA

[7] Yale Univ, Sch Med, Yale Canc Biol Inst, New Haven, CT USA

[8] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT USA

[9] Univ Connecticut, Sch Med, Dept Med, Div Nephrol, 263 Farmington Ave,L1062, Farmington, CT 06030 USA

来源：

JCI INSIGHT | 2023年 / 8卷 / 21期

关键词：

BETA-HYDROXYBUTYRATE; KETONE-BODIES; DELETION; DISEASE; SIRT5; FIBROBLASTS; INHIBITION; METABOLISM; ROLES;

D O I：

10.1172/jci.insight.170521

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 beta-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.

引用

页数：17