NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway contributing to pancreatic islet survival and function

Vázquez, Eugenia Martin; Cobo-Vuilleumier, Nadia; Legido, Raquel Araujo; Marín-Cañas, Sandra; Nola, Emanuele; Dorronsoro, Akaitz; Bermudo, Lucia López; Crespo, Alejandra; Romero-Zerbo, Silvana Y.; García-Fernández, María; Montalvo, Alejandro Martín; Rojas, Anabel; Comaills, Valentine; Bermúdez‐Silva, Francisco Javier; Gannon, Maureen; Martı́n, Franz; Eizirik, Décio L.; Lorenzo, Petra I.; Gauthier, Benoit R.

doi:10.1016/j.isci.2022.104345

Cited by 16 publications

(17 citation statements)

References 77 publications

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“…In this study, we also found that the expression of podocyte nuclear transcription factor LRH‐1 was downregulated in diabetic podocytes. Similarly, previous studies in patients or animal models with diabetes and nonalcoholic fatty liver disease (NAFLD) have found downregulation of LRH‐1 expression in islets and the liver 34,35 . Additionally, evidence has shown that LRH‐1 plays a role in regulating mitochondrial dynamics and a multitude of metabolic processes 36 .…”

Section: Discussionmentioning

confidence: 80%

“…Similarly, previous studies in patients or animal models with diabetes and nonalcoholic fatty liver disease (NAFLD) have found downregulation of LRH-1 expression in islets and the liver. 34,35 Additionally, evidence has shown that LRH-1 plays a role in regulating mitochondrial dynamics and a multitude of metabolic processes. 36 Here, we demonstrated that the expression of GLS2 in podocytes is regulated by LRH-1, and the activation or overexpression of LRH-1 can promote GLS2 expression and restore mitochondrial function, thereby reducing podocyte apoptosis, finally alleviating DKD-induced renal injury.…”

Section: Discussionmentioning

confidence: 99%

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LRH‐1 activation alleviates diabetes‐induced podocyte injury by promoting GLS2‐mediated glutaminolysis

Zhang

et al. 2023

Cell Proliferation

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Alteration of metabolic phenotype in podocytes directly contributes to the development of albuminuria and renal injury in conditions of diabetic kidney disease (DKD). This study aimed to identify and evaluate liver receptor homologue‐1 (LRH‐1) as a possible therapeutic target that alleviates glutamine (Gln) metabolism disorders and mitigates podocyte injury in DKD. Metabolomic and transcriptomic analyses were performed to characterize amino acid metabolism changes in the glomeruli of diabetic mice. Next, Western blotting, immunohistochemistry assays, and immunofluorescence staining were used to detect the expression of different genes in vitro and in vivo. Furthermore, Gln and glutamate (Glu) content as well as ATP generation were examined. A decrease in LRH‐1 and glutaminase 2 (GLS2) expression was detected in diabetic podocytes. Conversely, the administration of LRH‐1 agonist (DLPC) upregulated the expression of GLS2 and promoted glutaminolysis, with an improvement in mitochondrial dysfunction and less apoptosis in podocytes compared to those in vehicle‐treated db/db mice. Our study indicates the essential role of LRH‐1 in governing the Gln metabolism of podocytes, targeting LRH‐1 could restore podocytes from diabetes‐induced disturbed glutaminolysis in mitochondria.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

LRH‐1 activation alleviates diabetes‐induced podocyte injury by promoting GLS2‐mediated glutaminolysis

Zhang

et al. 2023

Cell Proliferation

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“…NR5A2 stabilizes acinar properties, prevents inflammation, and is required for acinar recovery after injury. NR5A2 expression is downregulated in metabolic syndrome [26]. Relevant literature reports that NR5A2 interacts with glucocorticoid receptors to regulate glucocorticoid resistance [23,27].…”

Section: Discussionmentioning

confidence: 99%

NR5A2 as a potential target for exercise to improve metabolic syndrome

Meng

Fang

Deng

2023

Aging

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Background: Metabolic syndrome is a syndrome of a variety of metabolic disorders. Exercise is beneficial to the human body. However, the association of NR5A2 and exercise with metabolic syndrome remains unclear. Methods: Download the GSE10540 and GSE12385 from GEO database. Bioinformatics analysis was used to screen the hub molecular of the metabolic syndrome. Forty 3-week-old C57BL/6J male mice were used in this study. The mean body weight was (17.5 ± 2.1) g. After 10 days of adaptive feeding, they were randomly divided into 4 groups according to the random number table method: Model + Exercise (n = 10), Model (n = 10), Model/NR5A2-OE (n = 10), Model/NR5A2-KO (n = 10). Western Blotting was performed to detect the expression of hub genes and signaling pathway. Results: There were 349 DEGs in GSE10540 and 49 DEGs in GSE12385. 10 core genes were obtained. GO showed that differentially expressed genes were mainly enriched in vascular morphogenesis, contractile fiber fraction, chemotaxis, and MAPK cascade regulation. KEGG showed that MAPK signaling pathway was a significant section in the metabolic syndrome. PIK3R2, STRA8, FLT1, DMRT1, FGF22, NR5A2, and FLT were up-regulated and PRDM14, POU5F1, and KDR were down-regulated in metabolic syndrome after exercise. Conclusion: The expression of NR5A2 is down-regulated in metabolic syndrome, and exercise can increase the expression level of NR5A2. NR5A2 might be used as a potential target for exercise to improve metabolic syndrome.

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“…Significant downregulation of prostaglandin E receptor 1 (PTGER1) in BRNPtreated mice reinforces our theory, as they are known to be highly expressed during COX-2 signaling when prostaglandin E2 is secreted. [42][43][44][45][46] Moreover, treatment with BRNPs upregulated cellular component category genes that encode elements of the haptoglobin-hemoglobin and hemoglobin complexes. The RNAseq results suggest that one possible mechanism of action of BRNPs in the LL-37-induced rosacea mouse model is increasing the expression of antioxidant defense genes by upregulating hemoglobin-bilirubin metabolism as well as alleviating inflammation by directly supplementing antioxidant capacity at the site of inflammation, as evidenced by the evaluation of BRNP localization.…”

Section: Discussionmentioning

confidence: 99%

Bilirubin Nanomedicine Alleviates Inflammation and Angiogenesis in a Rosacea Mouse Model

Choi

Keum

Yang

et al. 2023

Advanced Therapeutics

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Rosacea is a common chronic inflammatory facial disorder. Reactive oxygen species (ROS) have a key role in the pathogenesis of rosacea. In this study, the antioxidant and anti‐inflammatory effects of bilirubin‐based nanoparticles (BRNPs) are investigated in the LL‐37‐induced rosacea‐like mouse model. Effects of BRNPs on rosacea‐like skin inflammation and ROS level of the skin are determined using histological analysis. The expression of genes encoding rosacea‐associated cytokines and chemokines is assessed and the molecular mechanisms of BRNPs against rosacea are investigated using RNA sequencing (RNAseq) analysis. This study reveals that BRNPs significantly alleviate LL‐37‐induced inflammatory manifestation in the rosacea mouse model and reduce the expression of proinflammatory cytokines (interleukin [IL]‐1β, IL‐6, and tumor necrosis factor [TNF]‐α) and chemokines (C‐X‐C motif chemokine ligand 8 [CXCL8] and CXCL10). Moreover, BRNPs preferentially localize at the inflammatory skin lesion, decrease the level of ROS in the skin, and ameliorate the vascular endothelial growth factor expression and vascular changes in the skin induced by LL‐37. Furthermore, these findings provide a mechanism for the efficacy of BRNPs in this experimental model and support BRNPs as a potential therapeutic option for rosacea and other related inflammatory skin disorders.

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NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway contributing to pancreatic islet survival and function

Cited by 16 publications

References 77 publications

LRH‐1 activation alleviates diabetes‐induced podocyte injury by promoting GLS2‐mediated glutaminolysis

LRH‐1 activation alleviates diabetes‐induced podocyte injury by promoting GLS2‐mediated glutaminolysis

NR5A2 as a potential target for exercise to improve metabolic syndrome

Bilirubin Nanomedicine Alleviates Inflammation and Angiogenesis in a Rosacea Mouse Model

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