Calponin 2 harnesses metabolic reprogramming to determine kidney fibrosis

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

doi:10.1016/j.molmet.2023.101712

Cited by 6 publications

(10 citation statements)

References 47 publications

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“…Intriguingly, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and Gene Ontology (GO) analyses indicated that metabolic pathways were the most affected biological processes in shCNN2 diseased kidneys ( Figure 4, C and D ). Our earlier study showed that CNN2 knockdown activated the FAO pathway in CKD ( 5 ). Surprisingly, after AKI, none of the key FAO members were substantially changed between ShNC and ShCNN2 kidneys ( Figure 4E ).…”

Section: Resultsmentioning

confidence: 99%

“…Over the past several years, sporadic reports revealed the translational value of CNN2 from the perspective of cell mechanics, such as inhibiting tumor metastasis ( 3 ). Emerging evidence indicates that CNN2 is linked to various fibrotic processes, such as postoperative peritoneal adhesions and kidney fibrosis ( 4 , 5 ). In chronic kidney disease (CKD), CNN2 regulates energy metabolism by interacting with estrogen receptor 2 (ESR2) to control fibrosis progression ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

“…Emerging evidence indicates that CNN2 is linked to various fibrotic processes, such as postoperative peritoneal adhesions and kidney fibrosis ( 4 , 5 ). In chronic kidney disease (CKD), CNN2 regulates energy metabolism by interacting with estrogen receptor 2 (ESR2) to control fibrosis progression ( 5 ). Therefore, it would be worthwhile to fully dissect the role of CNN2 in acute kidney injury (AKI), given that AKI and CKD are closely intertwined but have distinct pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…During tubule repair, neighboring fibroblasts emerge as orchestrators of a favorable kidney local microenvironment (KLM) ( 6 ). In CKD, CNN2 is predominantly expressed in fibroblasts/pericytes, and knockdown of CNN2 alleviates kidney fibrosis by enhancing fatty acid oxidation (FAO) ( 5 ). Surprisingly, after AKI, our proteomics showed that CNN2 knockdown had a minor effect on FAO but markedly induced 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) in the kidney, a rate-limiting enzyme in ketogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Calponin 2 regulates ketogenesis to mitigate acute kidney injury

Gui,

Palanza,

Gupta

et al. 2023

JCI Insight

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Calponin 2 regulates ketogenesis to mitigate acute kidney injury

Gui,

Palanza,

Gupta

et al. 2023

JCI Insight

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“…According to recent research evidence, the link between metabolic reprogramming and kidney disease may have a profound impact on disease progression and patient prognosis [ 3 , 4 ]. The metabolic-regulating effects of SGLT2 inhibition have been demonstrated; however, further investigation is required to elucidate the precise underlying mechanism [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

SGLT2 inhibition, high-density lipoprotein, and kidney function: a mendelian randomization study

Wang,

Wei,

Zhao

et al. 2024

Lipids Health Dis

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Background Sodium-glucose cotransporter 2 (SGLT2) inhibition is recognized for its evident renoprotective benefits in diabetic renal disease. Recent data suggest that SGLT2 inhibition also slows down kidney disease progression and reduces the risk of acute kidney injury, regardless of whether the patient has diabetes or not, but the mechanism behind these observed effects remains elusive. The objective of this study is to utilize a mendelian randomization (MR) methodology to comprehensively examine the influence of metabolites in circulation regarding the impact of SGLT2 inhibition on kidney function. Methods We used a MR study to obtain associations between genetic proxies for SGLT2 inhibition and kidney function. We retrieved the most recent and comprehensive summary statistics from genome-wide association studies (GWAS) that have been previously published and involved kidney function parameters such as estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and albuminuria. Additionally, we included blood metabolite data from 249 biomarkers in the UK Biobank for a more comprehensive analysis. We performed MR analyses to explore the causal relationships between SGLT2 inhibition and kidney function and two-step MR to discover potential mediating metabolites. Results The study found that a decrease in HbA1c levels by one standard deviation, which is genetically expected to result in SGLT2 inhibition, was linked to a decreased likelihood of developing type 2 diabetes mellitus (T2DM) (odds ratio [OR] = 0.55 [95% CI 0.35, 0.85], P = 0.007). Meanwhile, SGLT2 inhibition also protects eGFR (β = 0.05 [95% CI 0.03, 0.08], P = 2.45 × 10− 5) and decreased UACR (-0.18 [95% CI -0.33, -0.02], P = 0.025) and albuminuria (-1.07 [95% CI -1.58, -0.57], P = 3.60 × 10− 5). Furthermore, the study found that of the 249 metabolites present in the blood, only one metabolite, specifically the concentration of small high-density lipoprotein (HDL) particles, was significantly correlated with both SGLT2 inhibition and kidney function. This metabolite was found to play a crucial role in mediating the improvement of renal function through the use of SGLT2 inhibition (β = 0.01 [95% CI 0.005, 0.018], P = 0.001), with a mediated proportion of 13.33% (95% CI [5.71%, 26.67%], P = 0.020). Conclusions The findings of this investigation provide evidence in favor of a genetically anticipated biological linkage between the inhibition of SGLT2, the presence of circulating metabolites, and renal function. The findings demonstrate that the protective effect of SGLT2 inhibition on renal function is mostly mediated by HDL particle concentrations in circulating metabolites. These results offer significant theoretical support for both the preservation of renal function and a better comprehension of the mechanisms underlying SGLT2 inhibition.

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