The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII

Abstract

Background Pericyte-myofibroblast transition (PMT) has been confirmed to contribute to renal fibrosis in several kidney diseases, and transforming growth factor-β1 (TGF-β1) is a well-known cytokine that drives PMT. However, the underlying mechanism has not been fully established, and little is known about the associated metabolic changes. Methods Bioinformatics analysis was used to identify transcriptomic changes during PMT. PDGFRβ + pericytes were isolated using MACS, and an in vitro model of PMT was induced by 5 ng/ml TGF-β1. Metabolites were analyzed by ultraperformance liquid chromatography (UPLC) and tandem mass spectrometry (MS). 2-Deoxyglucose (2-DG) was used to inhibit glycolysis via its actions on hexokinase (HK). The hexokinase II (HKII) plasmid was transfected into pericytes for HKII overexpression. LY294002 or rapamycin was used to inhibit the PI3K-Akt-mTOR pathway for mechanistic exploration. Results An increase in carbon metabolism during PMT was detected through bioinformatics and metabolomics analysis. We first detected increased levels of glycolysis and HKII expression in pericytes after stimulation with TGF-β1 for 48 h, accompanied by increased expression of α-SMA, vimentin and desmin. Transdifferentiation was blunted when pericytes were pretreated with 2-DG, an inhibitor of glycolysis. The phosphorylation levels of PI3K, Akt and mTOR were elevated during PMT, and after inhibition of the PI3K-Akt-mTOR pathway with LY294002 or rapamycin, glycolysis in the TGF-β1-treated pericytes was decreased. Moreover, PMT and HKII transcription and activity were blunted, but the plasmid-mediated overexpression of HKII rescued PMT inhibition. Conclusions The expression and activity of HKII as well as the level of glycolysis were increased during PMT. Moreover, the PI3K-Akt-mTOR pathway regulates PMT by increasing glycolysis through HKII regulation.

Hypoxic Inducible Factor Stabilization in Pericytes beyond Erythropoietin Production: The Good and the Bad

“…According to Chen et al, the pericyte-to-myofibroblast (PTM) transition mediated by TGF-β1 is characterized by increased glycolysis and elevated phosphorylation levels of serin threonine kinase mTOR. The inhibition of the PI3K-Akt-mTOR pathway resulted in decreased glycolysis, suggesting that this pathway plays a role in the regulation of PTM [67]. These results are consistent with studies in AKI animal models obtained by IRI.…”

AMPK signaling inhibits the differentiation of myofibroblasts: impact on age-related tissue fibrosis and degeneration

“…In addition to the Smad2/3 pathway, it seems that there also exist other inhibitory mechanisms driven by AMPK signaling. For instance, there is clear evidence indicating that TGF-β treatment can trigger myofibroblast differentiation via the PI3K/AKT/mTOR signaling pathway (Tang et al 2023 ; Chen et al 2023 ). For instance, Chen et al ( 2023 ) demonstrated that exposure to TGF-β induced the conversion of mouse renal pericytes into myofibroblasts.…”

“…For instance, there is clear evidence indicating that TGF-β treatment can trigger myofibroblast differentiation via the PI3K/AKT/mTOR signaling pathway (Tang et al 2023 ; Chen et al 2023 ). For instance, Chen et al ( 2023 ) demonstrated that exposure to TGF-β induced the conversion of mouse renal pericytes into myofibroblasts. The TGF-β treatment of pericytes robustly increased the expression of hexokinase II which enhanced the amount of glycolysis in converted myofibroblasts.…”

“…It is known that aerobic glycolysis is the major energy metabolic pathway utilized by myofibroblasts (Xie et al 2015 ). Chen et al ( 2023 ) also reported that the inhibition of either glycolytic flux or the activity of PI3K/AKT/mTOR signaling suppressed the conversion of the TGF-β-stimulated myofibroblasts, indicating that this pathway is an alternative route for myofibroblast differentiation. Moreover, Tang et al ( 2023 ) revealed that the TGF-β-induced PI3K/AKT/mTOR signaling induced the differentiation of canine valvular interstitial cells into myofibroblasts which displayed a phenotype with a reduced capacity for autophagy and an increase in senescence-associated secretory functions.…”

Effects of altered glycolysis levels on CD8+ T cell activation and function

“…Under the sufficient oxygen condition, pyruvate is oxidized by pyruvate dehydrogenase to produce acetyl coenzyme A, which enters the tricarboxylic acid (TCA) cycle and OXPHOS; whereas when oxygen is absen, pyruvate is catalyzed by lactate dehydrogenase to produce lactate [ 29 ]. Increasingly, it has been shown that in addition to the significant effects of changes in kinase activity on glycolytic activity and cell growth [ 30 ], signaling pathways such as PI3K/AKT/mTOR also play an important role in cell survival and development by mediating glycolysis-related processes [ 31 ]. An increasing number of studies have shown that changes in CD8 + T cells’ glycolysis and OXPHOS have different regulatory effects on CD8 + T cell activation, differentiation, and function.…”