Calponin 2 harnesses metabolic reprogramming to determine kidney fibrosis

Abstract

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. 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, Calponin 2 (CNN2) is predominantly expressed in fibroblasts and pericytes. 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 diseased kidneys. Inhibiting carnitine palmitoyltransferase 1α in the FAO pathway results in lipid accumulation and extracellular matrix deposition in the fibrotic kidneys, which were restored after CNN2 knockdown. In patients, increased serum CNN2 levels are correlated with lipid content. 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. Consequently, activation of PPARα reduced CNN2-induced matrix inductions. Our results suggest that balancing cell mechanics and metabolism is crucial to develop therapeutic strategies to halt kidney fibrosis.

Calponin 2 regulates ketogenesis to mitigate acute kidney injury

“…Understanding CNN2-mediated discrete fine-tuning of protein posttranslational modification is critical to optimize organ performance after AKI. JCI Insight 2023;8 (21):e170521 https://doi.org/10.1172/jci.insight.170521 (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.…”

“…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).…”

“…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.…”

Proteome characterization of liver–kidney comorbidity after microbial sepsis

“…Immunohistochemical staining showed protein expression patterns consistent with western blot assays of the septic livers (Figure 3F). Given the liver is the central organ that controls lipid homeostasis, we further examined the expression of a prominent protein linked to lipid deposition, perilipin 2, 40,41 in the septic livers. Perilipin 2 was dramatically induced at d2 after CLP and reduced to basal level at d7 (Figure 3G,H), consistent with our finding in the global proteomic analysis.…”

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

“…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].…”