Journal of molecular endocrinology最新文献

{"title":"Metabolic-renal disease genetic architecture revealed by genomic structural equation modeling.","authors":"Kaixi Ding, Li Xiang, Wei Jiang, Ming Lei, Yongxiang Gao","doi":"10.1530/JME-25-0171","DOIUrl":"10.1530/JME-25-0171","url":null,"abstract":"<p><p>Physiologic mechanisms underlying metabolic and renal diseases interact and are highly comorbid, yet their genetic associations and underlying mechanisms have not been systematically elucidated. Using genome-wide association study (GWAS) summary statistics from UK Biobank, FinnGen, and CKDGen, we integrated and analyzed gout, serum urate, chronic kidney disease, kidney stones, and metabolic syndrome. Using genomic structural equation modeling (GSEM), we created the first genetic linkage map for 'gout-urate-kidney-metabolism' (GUKM) to explore shared genetic architecture. Post-GWAS analyses for GUKM-GSEM GWAS, including functional annotation, enrichment, fine-mapping, causal inference, and gsMap, identified key genetic loci, pathways, tissues/cell types, and potential drug targets. We identified 164 lead SNPs, including rs1260326 (chr2) and rs73607783 (chr8), with GSEA showing significant enrichment of GUKM-GSEM GWAS in cholesterol metabolism and lipid pathways (adjP < 0.05). Tissue and cell enrichment highlighted the liver, renal cortex, pancreas, proximal tubular epithelial cells, and hepatocytes (P < 0.05). Mendelian randomization indicated a potential causal role of GCKR (FDR < 0.05), which gsMap showed to be highly expressed in hepatocytes and liver tissue. The present study revealed the common genetic basis of metabolic and renal diseases and emphasized that lipid metabolism may be a key intermediary pathway connecting the 'metabolic-renal axis'. The liver, renal cortex, and pancreas were the primary enriched tissues, and GCKR was identified as a core gene and potential drug target. Overall, this study provides an important reference for the genetic mechanisms, key mechanisms, and intervention targets of related diseases.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiolipin alleviates insulin resistance by ameliorating mitochondrial dysfunction and promoting fatty acid oxidation.","authors":"Chengcheng Yao, Jianglan Long, Yueyue Wang, Xiaojia Liu, Tingting Qiu, Kuan Chen, Dan Yan","doi":"10.1530/JME-25-0103","DOIUrl":"10.1530/JME-25-0103","url":null,"abstract":"<p><p>Cardiolipin deficiency is closely associated with mitochondrial dysfunction and metabolic disorders, yet whether it directly modulates insulin resistance remains unknown. Here, we examined the effects of cardiolipin supplementation on insulin resistance and the underlying mechanisms using male C57BL/6J mice fed a high-fat diet, male db/db mice, and dexamethasone-induced insulin-resistant HepG2 cells, a well-established model for investigating hepatic insulin signaling. Intragastric administration of cardiolipin at 5 mg/kg lowered blood glucose, reduced weight gain, improved insulin sensitivity, and alleviated hepatic lipid accumulation in mice, along with decreased serum interleukin-6 and low-density lipoprotein cholesterol levels. Cardiolipin reduced the LC3-II/LC3-I ratio and Tom20 expression in both liver tissue and insulin-resistant HepG2 cells, indicative of enhanced mitophagy. In HepG2 cells, it also attenuated mitochondrial fragmentation, improved mitochondrial membrane potential, lowered reactive oxygen species production, and upregulated the expression of CPT1A and ACAD1. These findings demonstrate that cardiolipin mitigates hepatic insulin resistance by enhancing mitophagy and fatty acid oxidation, representing a promising therapeutic approach for insulin resistance-related metabolic disorders.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the molecular landscape of the placenta in maternal diabetes: a systematic review of high-throughput data.","authors":"Georgia Fakonti, Abigail R Byford, Eleanor M Scott, Beth Holder, Karen Forbes","doi":"10.1530/JME-25-0131","DOIUrl":"10.1530/JME-25-0131","url":null,"abstract":"<p><p>Diabetes in pregnancy is associated with significant short- and long-term complications for mothers and offspring, many of which are thought to result from altered placental development and function. Although studies have demonstrated molecular changes in the placenta in this context, the precise mechanisms remain unclear. High-throughput transcriptomic and proteomic approaches provide powerful tools to systematically identify disease-associated pathways, yet no systematic synthesis of this literature has been undertaken. We conducted a systematic review of omics studies examining placental molecular changes in pregnancies complicated by diabetes compared with uncomplicated pregnancies. Fifty-six studies were eligible for inclusion, the majority of which focused on gestational diabetes mellitus (GDM; n = 52). Of these, 42 reported changes in RNA (n = 30) or protein (n = 12) abundance, with eight proteins and 189 RNA species consistently altered in at least two studies. Functional enrichment analysis revealed dysregulation of immune, vascular, and developmental pathways. Notably, 98 molecules were altered at both RNA and protein levels, 47 with consistent directionality across studies, suggesting robust disruption of core biological pathways. Comparisons across diabetes types showed partial overlap of differentially expressed transcripts between GDM and type 1 diabetes (16 genes) and GDM and type 2 diabetes (34 genes), although no universal markers were identified. These findings highlight shared molecular signatures in GDM, provide novel insights into pathways linking maternal diabetes to placental dysfunction and adverse outcomes, and emphasise the need for further studies on type 1 and type 2 diabetes. These pathways may represent potential therapeutic targets to mitigate intergenerational cardiometabolic risk.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147467911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A DYRK inhibitor ameliorates glucose homeostasis and increases incretin-producing cells in diabetic mice.","authors":"Michishige Terasaki, Qiao Zhou, Olov Andersson, Sho-Ichi Yamagishi","doi":"10.1530/JME-25-0214","DOIUrl":"10.1530/JME-25-0214","url":null,"abstract":"<p><p>Incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have been shown to improve hyperglycemia in patients with type 2 diabetes, suggesting that an enhanced capacity of GIP and GLP-1 production could be beneficial in type 2 diabetes. We have recently found that dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitors reduce glucose levels and increase the number of intestinal gip-expressing K-cells and glp-1-expressing L-cells in zebrafish. However, their effects on mammals require exploration in greater detail. In this study, we examined whether oral administration of a DYRK inhibitor, ID-8, to diabetic db/db mice affects glucose homeostasis, plasma levels of insulin, incretins, number of intestinal K-cells and L-cells and pancreatic cell volume in vivo. ID-8-treated mice showed a significant reduction in HbA1c levels and decreased blood glucose levels after oral glucose tolerance test along with enhanced plasma levels of insulin, total-GIP and total-GLP-1. The number of K-cells and L-cells in the intestines of ID-8-treated mice was increased, and a subset of these cells were co-stained with a DYRK-regulated transcriptional factor, nuclear factor of activated T cells 4 (NFATc4), but not co-localized with the proliferation marker EdU. There were no significant differences of pancreatic β- and α-cell mass between the ID-8- and vehicle-treated mice. Moreover, mRNA levels of incretins were significantly increased in ID-8-treated human intestinal organoids. Our present study demonstrated that ID-8 improved hyperglycemia in association with enhanced plasma levels of insulin and incretins as well as an increased number of K-cells and L-cells in diabetic mice; therefore, it may be a novel therapeutic agent for diabetes.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12978661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hormone- and cytokine-mediated signalling in the maintenance of bone balance.","authors":"Avinash M Yadav, Gunjan Patil, Samruddhi Zende, Snehal Bhumkar, Sneha Sagarkar, Bhaskar Saha, Richa Ashma","doi":"10.1530/JME-25-0123","DOIUrl":"10.1530/JME-25-0123","url":null,"abstract":"<p><p>Bones form the skeletal framework, enabling movement, mineral balance, and hematopoiesis. Bone remodelling - tightly controlled by hormones, cytokines, and growth factors - is a dynamic process involving different cell types: osteoclasts, osteoblasts, and osteocytes; disrupted remodelling leads to disorders such as osteoporosis, arthritis, rickets, and osteomalacia. This review examines how osteoblast differentiation and bone metabolism are influenced by important hormonal regulators, including parathyroid hormone (PTH), which is the key regulator, followed by the effect of calcitonin, vitamin D, and insulin-like growth factor-1 (IGF-1), cytokines including transforming growth factor-beta, bone morphogenetic proteins, and immune modulators such as cluster of differentiation 40 (CD40)/and its ligand (CD40L). Their signalling pathways converge on key transcription factors - Runt-related transcription factor 2 (RUNX2), Osterix, and osteoprotegerin - and regulators - such as SMAD (suppressor of mothers against decapentaplegic) and mitogen-activated protein kinases (MAPKs) - coordinating osteoblast differentiation, bone matrix deposition, and mineralisation. We distinguish the effects of intermittent versus continuous parathormone administration and emphasise the dual genomic and non-genomic vitamin D actions and factors affecting its receptor expression. The PTH-regulated wingless-related integration site (Wnt)/β-catenin signalling is decisive for osteogenesis, and iPTH and cPTH exert distinct effects on osteoblastogenesis. The signalling pathways - SMAD-independent and SMAD-dependent - that control osteogenesis are analysed. The immune co-receptor CD40 interacts with CD40L to impact both osteoblasts and osteoclasts, linking immune responses and inflammation to bone health alterations. IGF-1 modulates osteoblast development and proliferation through mitogen-activated protein kinase (MEK) pathways. Understanding the molecular interactions among these pathways provides valuable insights into possible therapeutic targets for managing bone regeneration and bone disorders.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"76 2","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147433624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Localisation of corticosteroids in male mouse kidney by mass spectrometry imaging.","authors":"Ioannis Stasinopoulos, Shazia Khan, Shaden Melhem, Martin Roumain, Diego F Cobice, Natalie Z M Homer, C Logan Mackay, Roger W Brown, Matthew A Bailey, Ruth Andrew","doi":"10.1530/JME-25-0099","DOIUrl":"10.1530/JME-25-0099","url":null,"abstract":"<p><strong>Abstract: </strong>Renal sodium balance is important for blood pressure homoeostasis and is regulated by corticosteroids, chiefly aldosterone but also glucocorticoids. Abundance of these hormones in functional subregions of the kidney is unknown, previous work being limited to measurements in plasma and urine, and in microdialysate from kidney medulla. Here, mass spectrometry imaging (MSI) was applied to map corticosteroids in kidney to understand how their distribution overlays with functional targets. Male C57BL/6J mice, aged 10 weeks, were fed diets containing 0.03, 0.3 or 3% w:w sodium for two weeks, and kidneys harvested at cull. Steroids were localised as Girard T derivatives on cryosections using matrix-assisted laser desorption ionisation Fourier transform ion cyclotron MSI, with confirmation by liquid extraction surface analysis. Co-registration was performed on sections stained with haematoxylin and eosin. Corticosterone localised along the papilla, medulla and inner cortex, whereas 11-dehydrocorticosterone was concentrated in the medulla. Higher amounts of aldosterone were present in the medulla and outer cortex. Distribution patterns were unchanged by dietary salt, but amounts of corticosterone were elevated, particularly in the outer cortex with a low-salt diet. MSI holds great promise to dissect corticosteroid signalling in functional zones of the kidney.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12927002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Laboratory diagnostics and follow-up of medullary thyroid cancer.","authors":"Luca Giovanella, Federica D'Aurizio, Petra Petranović Ovčariček, Jacquelien J Hillebrand","doi":"10.1530/JME-25-0185","DOIUrl":"10.1530/JME-25-0185","url":null,"abstract":"<p><p>Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy of thyroid C-cells characterized by the secretion of several circulating biomarkers, including calcitonin (CT), procalcitonin (PCT), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and pro-gastrin-releasing peptide (proGRP). These analytes substantially contribute to the diagnosis, postoperative monitoring, and prognostic stratification of MTC. Nevertheless, their optimal use remains limited by analytical, pre-analytical, and biological factors that can compromise result reliability and clinical interpretation. Despite improvements in assay technology, significant inter-method variability persists for CT and CA 19-9, while heterophile antibodies, macro-analyte formation, renal dysfunction, and pharmacologic influences may cause spurious or misleading results. Moreover, a lack of harmonized reference intervals and clinical decision thresholds complicates longitudinal follow-up and inter-laboratory comparison. This review systematically addresses current laboratory challenges affecting MTC biomarkers, summarizes the main sources of false-positive or unreliable results, and discusses the complementary diagnostic roles of CT, PCT, and emerging analytes such as proGRP. Emphasis is placed on standardization needs, verification of analytical performance, and the importance of consistent assay use in patient follow-up. Ultimately, the effective management of MTC biomarkers requires active engagement of clinical chemists and pathologists within multidisciplinary teams to ensure accurate interpretation, resolve analytical ambiguities, and integrate biochemical data into evidence-based therapeutic decision-making.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linoleic acid reduces sodium-iodide symporter by inhibiting endoplasmic reticulum stress in papillary thyroid carcinoma.","authors":"Nianting Ju, Yumin Liu, Fan Yu, Chuang Xi, Hongjun Song, Zhongling Qiu, Quanyong Luo, Chentian Shen","doi":"10.1530/JME-25-0135","DOIUrl":"10.1530/JME-25-0135","url":null,"abstract":"<p><p>Novel biomarkers are imperative for predicting radioactive iodine (RAI) avidity in metastatic lesions of differentiated thyroid carcinoma, and mechanisms regulating RAI uptake remain incompletely understood. This study aimed to identify distinct serum metabolic profiles in papillary thyroid carcinoma (PTC) patients with non-131I-avid disease and elucidate underlying molecular mechanisms. Serum samples from 94 PTC patients were analyzed using gas chromatography-time-of-flight mass spectrometry. Patients were stratified into the non-131I-avid pulmonary metastases group (n = 30), the 131I-avid pulmonary metastases group (n = 31), and the remnant ablation group (n = 33). Principal component analysis and orthogonal partial least squares-discriminant analysis was employed for classification and biomarker identification. Differential metabolites were visualized via heatmap and evaluated for diagnostic potential using receiver operating characteristic curve analysis. Pathway enrichment analysis utilized the KEGG database. Sixty metabolites were significantly dysregulated between non-131I-avid and 131I-avid groups: 54 elevated (fold change (FC) range: 1.17-4.81) and 6 reduced (FC range: 0.31-0.82) in the non-131I-avid cohort. Ten metabolites demonstrated a high predictive power for non-131I-avid pulmonary metastatic PTC (AUC > 0.9; P < 0.001). Pathway analysis identified linoleic acid (LA) metabolism as the most significantly altered pathway (impact factor = 1.0). Mechanistically, LA competitively inhibited the binding of the endoplasmic reticulum (ER) stress-responsive transcription factor ATF4 to the sodium-iodide symporter (NIS) promoter, suppressing NIS transcription. Serum metabolomic profiling effectively discriminates PTC patients with pulmonary metastases based on 131I avidity. Our findings demonstrate that LA attenuates NIS expression by inhibiting ER stress-mediated ATF4 activation in PTC. This work provides novel mechanistic insights into non-131I-avid metastatic PTC development and identifies potential diagnostic biomarkers and therapeutic targets.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic effect of IL-11 inhibition on the pathogenesis of thyroid eye disease.","authors":"Hee Joo Yoon, Hyun Young Park, Ji-Young Kim, Soo Hyun Choi, Don O Kikkawa, James S Swaney, David J King, Yasmin M Vasquez, Jin Sook Yoon","doi":"10.1530/JME-25-0080","DOIUrl":"10.1530/JME-25-0080","url":null,"abstract":"<p><p>Thyroid eye disease (TED), a major extrathyroidal manifestation of Graves' disease, is driven by the underlying autoimmune responses. This study aimed to elucidate the pathological role of IL-11 in TED and evaluate the therapeutic potential of LASN01, a potent, fully human antibody that targets IL-11 receptor alpha (IL-11Rα). IL-11 (P < 0.001) and IL-11Rα (P = 0.003) mRNA were significantly elevated in TED orbital tissues (n = 15) compared to normal controls (n = 15) by quantitative real-time polymerase chain reaction (RT-qPCR). IL-11 expressions in both TED and normal orbital fibroblasts (OFs) were upregulated after treatment with either transforming growth factor-beta (TGF-β) or insulin-like growth factor 1 (IGF-1). Furthermore, IL-11 exerted a synergistic stimulatory effect on hyaluronan production in TED OFs when combined with either TGF-β (3.21-fold, P < 0.001) or IGF-1 (2.83-fold, P < 0.001). Notably, the combination of IL-11 and TGF-β induced greater procollagen production (6.17-fold, P < 0.001). Blocking IL-11R with LASN01 effectively reduced both hyaluronan (94% reduction, P < 0.001) and procollagen production (36% reduction, P = 0.002) in ELISA under various stimulation conditions. Finally, Western blot analysis showed that LASN01 blocked STAT3 and ERK phosphorylation in TED OFs, which are known as downstream effectors of IL-11 signaling. This study systematically analyzed how IGF-1 and TGF-β promote IL-11 expression in OFs and examined the downstream effects of IL-11 on hyaluronan and procollagen production, highlighting the central role of IL-11 in TED-associated tissue expansion and fibrosis. The inhibitory effects of LASN01 on hyaluronan and procollagen production suggest that targeting IL-11R could represent an effective therapeutic option for TED, providing a foundation for future clinical applications.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinoic acid receptor β deletion in podocytes causes kidney and liver dysfunction, modeling nephrotic syndrome.","authors":"Yuling Chi, Krysta M DiKun, Xiao-Han Tang, Charles D Warren, Shireen Chikara, Eduardo Mere Del Aguila, John A Wagner, Jacob B Geri, Lorraine J Gudas","doi":"10.1530/JME-25-0146","DOIUrl":"10.1530/JME-25-0146","url":null,"abstract":"<p><p>Differentially altered expression of transcripts of retinoic acid receptors α, β, γ (Rarα, β, γ), which mediate the actions of all-trans retinoic acid (RA), is observed in glomeruli of nephrotic syndrome (NS) patients vs normal individuals, with Rarβ reduced and both RARα and RARγ increased. Thus, we generated a mouse model (PCRB) with Rarβ specifically deleted in podocytes to define the glomerular actions of Rarβ. Rarβ deletion in PCRB mice results in podocyte loss, podocyte foot process effacement, glomerular basement membrane (GBM) thickening, reduced podocyte adhesion to the GBM, lipid accumulation in glomeruli, and hyperfiltration leading to albuminuria. Genome-wide transcriptomics and proteomics studies of glomeruli revealed that Rarβ deletion increased Mogat, Dgat, and Hmgcs mRNAs, which catalyze triglyceride and cholesterol synthesis, and Slc27a2 and Cd36, which mediate fatty acid uptake, recapitulating NS symptoms. Surprisingly, podocyte-specific Rarβ deletion also increased key mRNAs and proteins involved in fatty acid uptake and lipid biosynthesis in the liver, promoting steatohepatitis and systemic hyperlipidemia. These data indicate that Rarβ signaling in the kidney has a profound impact on both kidney and liver functions and suggest that Rarβ plays an important role in regulating kidney-liver crosstalk. PCRB mice may be a useful model of NS.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12822819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}