Molecular mechanisms underlying the role of hypoxia-inducible factor-1 α in metabolic reprogramming in renal fibrosis

Wei, Xuejiao; Hou, Yue; Long, Mengtuan; Jiang, Lili; Du, Yujun

doi:10.3389/fendo.2022.927329

Cited by 25 publications

(19 citation statements)

References 131 publications

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“…One of the characteristics of DKD is ECM accumulation, which eventually leads to glomerular sclerosis and fibrosis ( Doi et al, 2018 ). Studies have demonstrated that HIF-1α promotes aberrant glycolysis, which finally leading to ECM accumulation and renal fibrosis in mouse models of chronic/hypoxic renal injury models ( Cai et al, 2020 ; Wei et al, 2022 ). Our diabetic db/db mice showed the pro-fibrotic activities in the kidney accompanied by kidney dysfunction and increased proteinuria and kidney injury in this study, indicating that our diabetic model presented with progressive DKD.…”

Section: Discussionmentioning

confidence: 99%

YY1-induced upregulation of LncRNA-ARAP1-AS2 and ARAP1 promotes diabetic kidney fibrosis via aberrant glycolysis associated with EGFR/PKM2/HIF-1α pathway

Ma²,

Wang³

et al. 2023

Front. Pharmacol.

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Objectives: Dimeric pyruvate kinase (PK) M2 (PKM2) plays an important role in promoting the accumulation of hypoxia-inducible factor (HIF)-1α, mediating aberrant glycolysis and inducing fibrosis in diabetic kidney disease (DKD). The aim of this work was to dissect a novel regulatory mechanism of Yin and Yang 1 (YY1) on lncRNA-ARAP1-AS2/ARAP1 to regulate EGFR/PKM2/HIF-1α pathway and glycolysis in DKD.Materials and methods: We used adeno-associated virus (AAV)-ARAP1 shRNA to knocked down ARAP1 in diabetic mice and overexpressed or knocked down YY1, ARAP1-AS2 and ARAP1 expression in human glomerular mesangial cells. Gene levels were assessed by Western blotting, RT-qPCR, immunofluorescence staining and immunohistochemistry. Molecular interactions were determined by RNA pull-down, co-immunoprecipitation, ubiquitination assay and dual-luciferase reporter analysis.Results: YY1, ARAP1-AS2, ARAP1, HIF-1α, glycolysis and fibrosis genes expressions were upregulated and ARAP1 knockdown could inhibit dimeric PKM2 expression and partly restore tetrameric PKM2 formation, while downregulate HIF-1α accumulation and aberrant glycolysis and fibrosis in in-vivo and in-vitro DKD models. ARAP1 knockdown attenuates renal injury and renal dysfunction in diabetic mice. ARAP1 maintains EGFR overactivation in-vivo and in-vitro DKD models. Mechanistically, YY1 transcriptionally upregulates ARAP1-AS2 and indirectly regulates ARAP1 and subsequently promotes EGFR activation, HIF-1α accumulation and aberrant glycolysis and fibrosis.Conclusion: Our results first highlight the role of the novel regulatory mechanism of YY1 on ARAP1-AS2 and ARAP1 in promoting aberrant glycolysis and fibrosis by EGFR/PKM2/HIF-1α pathway in DKD and provide potential therapeutic strategies for DKD treatments.

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Section: Discussionmentioning

confidence: 99%

YY1-induced upregulation of LncRNA-ARAP1-AS2 and ARAP1 promotes diabetic kidney fibrosis via aberrant glycolysis associated with EGFR/PKM2/HIF-1α pathway

Ma²,

Wang³

et al. 2023

Front. Pharmacol.

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“…Based on the difference in the α-subunits, HIFs are divided into three subtypes: HIF-1, HIF-2, and HIF-3. Reportedly, oxidative factors induced renal fibrosis by regulating the expression and activity of HIF-1 via PHD, ERK, and PI-3 K/AKT pathways [ 57 , 58 ]. Therefore, the MAPK, Ras, PI3K-Akt, FoxO, and HIF-1 signaling pathways are closely related to the occurrence and development of renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the potential biological mechanisms of diosmin against renal fibrosis based on network pharmacology and molecular docking approach

Zhao

Wang

Shi

et al. 2023

BMC Complement Med Ther

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Background Interstitial fibrosis is involved in the progression of various chronic kidney diseases and renal failure. Diosmin is a naturally occurring flavonoid glycoside that has antioxidant, anti-inflammatory, and antifibrotic activities. However, whether diosmin protects kidneys by inhibiting renal fibrosis is unknown. Methods The molecular formula of diosmin was obtained, targets related to diosmin and renal fibrosis were screened, and interactions among overlapping genes were analyzed. Overlapping genes were used for gene function and KEGG pathway enrichment analysis. TGF-β1 was used to induce fibrosis in HK-2 cells, and diosmin treatment was administered. The expression levels of relevant mRNA were then detected. Results Network analysis identified 295 potential target genes for diosmin, 6828 for renal fibrosis, and 150 hub genes. Protein–protein interaction network results showed that CASP3, SRC, ANXA5, MMP9, HSP90AA1, IGF1, RHOA, ESR1, EGFR, and CDC42 were identified as key therapeutic targets. GO analysis revealed that these key targets may be involved in the negative regulation of apoptosis and protein phosphorylation. KEGG indicated that pathways in cancer, MAPK signaling pathway, Ras signaling pathway, PI3K-Akt signaling pathway, and HIF-1 signaling pathway were key pathways for renal fibrosis treatment. Molecular docking results showed that CASP3, ANXA5, MMP9, and HSP90AA1 stably bind to diosmin. Diosmin treatment inhibited the protein and mRNA levels of CASP3, MMP9, ANXA5, and HSP90AA1. Network pharmacology analysis and experimental results suggest that diosmin ameliorates renal fibrosis by decreasing the expression of CASP3, ANXA5, MMP9, and HSP90AA1. Conclusions Diosmin has a potential multi-component, multi-target, and multi-pathway molecular mechanism of action in the treatment of renal fibrosis. CASP3, MMP9, ANXA5, and HSP90AA1 might be the most important direct targets of diosmin.

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“…Even in the absence of hyperglycemia, upregulation of mTOR and HIF-1 α promotes entry of glucose into cells through glucose transporter 1 (GLUT1) 10–14 ; the resulting increase in glucose-6-phosphate leads to further activation of mTOR 15,16 ; and HIF-1 α promotes downstream aerobic glycolysis and lactate formation as the major sources of ATP production. 14,17–19 At the same time, mTOR inhibits glucose and fatty acid oxidation by the mitochondria, 20 whose integrity is likely to be imperiled by the action of HIF-1 α and mTOR to generate reactive oxygen species. 21,22 Signaling through glucose-6-phosphate also activates the pentose phosphate pathway, thus providing ribose-5-phosphate required for nucleotide synthesis and entry into the cell cycle, 23–26 a process promoted by the increase in oxidative stress.…”

Section: Nutrient Surplus and Nutrient Deprivation Signaling In Cellu...mentioning

confidence: 99%

Fetal Reprogramming of Nutrient Surplus Signaling, O-GlcNAcylation, and the Evolution of CKD

Packer

2023

JASN

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Fetal kidneys have increased uptake of glucose, ATP production by glycolysis, and upregulation of mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF-1α). These interacting processes promote nephrogenesis in a hypoxic low-tubular-workload environment. In contrast, the healthy adult kidney upregulates sirtuin-1 and adenosine monophosphate-activated protein kinase, which enhances ATP production through fatty-acid oxidation, in a normoxic high-tubular-workload environment. During stress or injury, the kidney reverts to a fetal signaling program that is adaptive in the short-term, but deleterious if sustained with heightened oxygen tension and tubular workloads. Prolonged increase in glucose uptake in glomerular and proximal tubular cells leads to enhanced flux through the hexosamine biosynthesis pathway. The endproduct — uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) — drives the rapid and reversible O-GlcNAcylation of thousands of intracellular proteins, most not membrane-bound or secreted. O-GlcNAcylation and phosphorylation act at serine/threonine residues, but whereas hundreds of kinases and phosphatases regulate phosphorylation, only O-GlcNAc transferase and O-GlcNAcase, which add or remove O-GlcNAc from target proteins, regulate O-GlcNAcylation. Fetal reprogramming (upregulating mTOR and HIF-1α) and increased O-GlcNAcylation occur in diabetic and nondiabetic CKD, experimentally and clinically. Augmentation of O-GlcNAcylation in the adult kidney enhances oxidative stress, cell cycle entry, and apoptosis, activates proinflammatory and profibrotic pathways, and inhibits megalin-mediated albumin endocytosis in glomerular mesangial and proximal tubular cells, which muting of O-GlcNAcylation can aggravate and attenuate, respectively. Additionally, some nephroprotective drugs are associated with diminished O-GlcNAcylation in the kidney. Evidence supports further investigation of UDP-GlcNAc as a critical nutrient surplus sensor in the development of diabetic and nondiabetic CKD.

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Molecular mechanisms underlying the role of hypoxia-inducible factor-1 α in metabolic reprogramming in renal fibrosis

Cited by 25 publications

References 131 publications

YY1-induced upregulation of LncRNA-ARAP1-AS2 and ARAP1 promotes diabetic kidney fibrosis via aberrant glycolysis associated with EGFR/PKM2/HIF-1α pathway

YY1-induced upregulation of LncRNA-ARAP1-AS2 and ARAP1 promotes diabetic kidney fibrosis via aberrant glycolysis associated with EGFR/PKM2/HIF-1α pathway

Analysis of the potential biological mechanisms of diosmin against renal fibrosis based on network pharmacology and molecular docking approach

Fetal Reprogramming of Nutrient Surplus Signaling, O-GlcNAcylation, and the Evolution of CKD

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