JCI insight最新文献_第2页

Fasting substrates predict chronic kidney disease progression in CREDENCE trial patients with type 2 diabetes.

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-20 DOI: 10.1172/jci.insight.180637

Ele Ferrannini, Simona Baldi, Maria Tiziana Scozzaro, Giulia Ferrannini, Michael K Hansen

{"title":"Fasting substrates predict chronic kidney disease progression in CREDENCE trial patients with type 2 diabetes.","authors":"Ele Ferrannini, Simona Baldi, Maria Tiziana Scozzaro, Giulia Ferrannini, Michael K Hansen","doi":"10.1172/jci.insight.180637","DOIUrl":"https://doi.org/10.1172/jci.insight.180637","url":null,"abstract":"BACKGROUNDSodium-glucose cotransporter 2 inhibitors slow down progression of chronic kidney disease (CKD). We tested whether the circulating substrate mix is related to CKD progression and cardiovascular outcomes in patients with type 2 diabetes (T2D) and albuminuric CKD in the CREDENCE trial.METHODSWe measured fasting substrates in 2,543 plasma samples at baseline and 1 year after randomization to either 100 mg canagliflozin or placebo and used multivariate Cox models to explore their association with CKD progression, heart failure hospitalization/cardiovascular death (hHF/CVD), and mortality.RESULTSHigher baseline lactate and free fatty acids (FFAs) were independently associated with a lower risk of CKD progression (HR = 0.73 [95% CI: 0.54-0.98] and HR = 0.67 [95% CI: 0.48-0.95], respectively) and hHF/CVD HR = 0.70 [95% CI: 0.50-0.99] and HR = 0.63 [95% CI: 0.42-0.94]). Canagliflozin led to a rise in plasma FFAs, glycerol, β-hydroxybutyrate, and acetoacetate. Changes in substrate between baseline and year 1 predicted an approximately 30% reduction in relative risk of both CKD progression and hHF/CVD independently of treatment. More patients who did not respond to canagliflozin treatment in terms of CKD progression belonged to the bottom lactate and FFA distribution tertiles.CONCLUSIONIn T2D patients with albuminuric CKD, basic energy substrates selectively influenced major long-term endpoints; canagliflozin treatment amplified their effects by chronically raising their circulating levels.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 24","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting ketone body metabolism in mitigating gemcitabine resistance. 针对酮体代谢缓解吉西他滨耐药性。

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-20 DOI: 10.1172/jci.insight.177840

Krizia Rohena-Rivera, Sungyong You, Minhyung Kim, Sandrine Billet, Johanna Ten Hoeve, Gabrielle Gonzales, Chengqun Huang, Ashley Heard, Keith Syson Chan, Neil A Bhowmick

{"title":"Targeting ketone body metabolism in mitigating gemcitabine resistance.","authors":"Krizia Rohena-Rivera, Sungyong You, Minhyung Kim, Sandrine Billet, Johanna Ten Hoeve, Gabrielle Gonzales, Chengqun Huang, Ashley Heard, Keith Syson Chan, Neil A Bhowmick","doi":"10.1172/jci.insight.177840","DOIUrl":"10.1172/jci.insight.177840","url":null,"abstract":"Chemotherapy is often combined with surgery for muscle invasive and nonmuscle invasive bladder cancer (BCa). However, 70% of the patients recur within 5 years. Metabolic reprogramming is an emerging hallmark in cancer chemoresistance. Here, we report a gemcitabine resistance mechanism that promotes cancer reprogramming via the metabolic enzyme OXCT1. This mitochondrial enzyme, responsible for the rate-limiting step in β-hydroxybutyrate (βHB) catabolism, was elevated in muscle invasive disease and in patients with chemoresistant BCa. Resistant orthotopic tumors presented an OXCT1-dependent rise in mitochondrial oxygen consumption rate, ATP, and nucleotide biosynthesis. In resistant BCa, knocking out OXCT1 restored gemcitabine sensitivity, and administering the nonmetabolizable βHB enantiomer (S-βHB) only partially restored gemcitabine sensitivity. Suggesting an extrametabolic role for OXCT1, multi-omics analysis of gemcitabine sensitive and resistant cells revealed an OXCT1-dependent signature with the transcriptional repressor OVOL1 as a master regulator of epithelial differentiation. The elevation of OVOL1 target genes was associated with its cytoplasmic translocation and poor prognosis in a cohort of patients with BCa who have been treated with chemotherapy. The KO of OXCT1 restored OVOL1 transcriptional repressive activity by its nuclear translocation. Orthotopic mouse models of BCa supported OXCT1 as a mediator of gemcitabine sensitivity through ketone metabolism and regulating cancer stem cell differentiation.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SNRNP70 regulates the splicing of CD55 to promote osteosarcoma progression.

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-20 DOI: 10.1172/jci.insight.185269

Wenyue Li, Linzhu Wang, Wen Tian, Weihang Ji, Danyang Bing, Yan Wang, Bingqian Xu, Jiayue Feng, Peng Zhang, Haihai Liang, Yunyan Gu, Baofeng Yang

{"title":"SNRNP70 regulates the splicing of CD55 to promote osteosarcoma progression.","authors":"Wenyue Li, Linzhu Wang, Wen Tian, Weihang Ji, Danyang Bing, Yan Wang, Bingqian Xu, Jiayue Feng, Peng Zhang, Haihai Liang, Yunyan Gu, Baofeng Yang","doi":"10.1172/jci.insight.185269","DOIUrl":"https://doi.org/10.1172/jci.insight.185269","url":null,"abstract":"Osteosarcoma (OS) is the most common malignant bone tumor, characterized by a high propensity for metastasis. Recent studies have highlighted the role of alternative splicing in cancer metastasis, although the precise mechanisms underlying aberrant splicing in OS invasion and metastasis remain unclear. Here, we analyzed consistently differentially expressed genes and differentially alternative splicing events between primary and metastatic OS to identify potential genes associated with OS progression. U1 small nuclear ribonucleoprotein 70K (SNRNP70) emerged as both differentially expressed and spliced, with elevated SNRNP70 levels correlating with poor prognosis in pateints with OS. Functional experiments demonstrated that SNRNP70 overexpression enhanced the proliferation and metastasis of OS cells in vitro, while its depletion reduced these capabilities in vivo. Mechanistically, SNRNP70 directly interacted with CD55, modulating its alternative splicing and promoting tumor progression in OS. Additionally, metastatic OS samples exhibited increased infiltration of resting immune cells, and single-cell RNA sequencing revealed communication between SNRNP70-expressing osteoblastic cells and macrophages via the ADGRE5/CD55 signaling pathway. Overall, our results showed that SNRNP70 knockdown inhibited OS progression, which was associated with the splicing of CD55, indicating SNRNP70 as a promising target for OS treatment.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 24","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A randomized, double-blind, placebo-controlled study of a GHSR blocker in people with alcohol use disorder.

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-20 DOI: 10.1172/jci.insight.182331

Monica L Faulkner, Mehdi Farokhnia, Mary R Lee, Lisa Farinelli, Brittney D Browning, Kelly Abshire, Allison M Daurio, Vikas Munjal, Sara L Deschaine, Selim R Boukabara, Christopher Fortney, Garrick Sherman, Melanie Schwandt, Fatemeh Akhlaghi, Reza Momenan, Thomas J Ross, Susan Persky, Lorenzo Leggio

{"title":"A randomized, double-blind, placebo-controlled study of a GHSR blocker in people with alcohol use disorder.","authors":"Monica L Faulkner, Mehdi Farokhnia, Mary R Lee, Lisa Farinelli, Brittney D Browning, Kelly Abshire, Allison M Daurio, Vikas Munjal, Sara L Deschaine, Selim R Boukabara, Christopher Fortney, Garrick Sherman, Melanie Schwandt, Fatemeh Akhlaghi, Reza Momenan, Thomas J Ross, Susan Persky, Lorenzo Leggio","doi":"10.1172/jci.insight.182331","DOIUrl":"https://doi.org/10.1172/jci.insight.182331","url":null,"abstract":"BACKGROUNDStudies have demonstrated the role of ghrelin in alcohol-related behaviors and consumption. Blockade of the growth hormone secretagogue receptor (GHSR), which is the ghrelin receptor, has been shown to decrease alcohol drinking and reward-related behaviors across several animal models. We previously conducted a human study testing a GHSR inverse agonist/competitive antagonist, PF-5190457, in individuals who are heavy drinkers and showed its safety when coadministered with alcohol. Here, we conducted a phase IIa experimental medicine study in patients with alcohol use disorder (AUD) to investigate the effects of PF-5190457 on alcohol- and food-related outcomes.METHODSForty-two individuals with AUD (n = 29 completers) participated in a randomized, double-blind, placebo-controlled study where they received PF-5190457 100mg b.i.d. (or placebo) in 2 counterbalanced, within-subject stages. Participants completed an alcohol cue-reactivity (CR) experiment in a bar-like laboratory and a virtual food choice experiment in a cafeteria-like virtual reality (VR) environment. A subset of participants (n = 12) performed a CR task during a brain functional MRI (fMRI) experiment.RESULTSPF-5190457 did not reduce cue-elicited alcohol craving. PF-5190457 reduced virtual calories selected (P = 0.04) in the VR environment. PF-5190457 did not influence neural activation during CR task in the fMRI experiment.CONCLUSIONThis study provides human evidence of the role of GHSR blockade in behaviors related to food selection and highlights the need for future investigations into targeting the ghrelin system in AUD.TRIAL REGISTRATIONClinicalTrials.gov (accession no. NCT02707055).FUNDINGNIDA and NIAAA ZIA-DA000635; National Center for Advancing Translational Sciences UH2/UH3-TR000963.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 24","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Flotillin-2 dampens T cell antigen sensitivity and functionality. Flotillin-2 可抑制 T 细胞的抗原敏感性和功能。

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-20 DOI: 10.1172/jci.insight.182328

Sookjin Moon, Fei Zhao, Mohammad N Uddin, Charles J Tucker, Peer Wf Karmaus, Michael B Fessler

{"title":"Flotillin-2 dampens T cell antigen sensitivity and functionality.","authors":"Sookjin Moon, Fei Zhao, Mohammad N Uddin, Charles J Tucker, Peer Wf Karmaus, Michael B Fessler","doi":"10.1172/jci.insight.182328","DOIUrl":"10.1172/jci.insight.182328","url":null,"abstract":"T cell receptor (TCR) engagement triggers T cell responses, yet how TCR-mediated activation is regulated at the plasma membrane remains unclear. Here, we report that deleting the membrane scaffolding protein Flotillin-2 (Flot2) increases T cell antigen sensitivity, resulting in enhanced TCR signaling and effector function in response to weak TCR stimulation. T cell-specific Flot2-deficient mice exhibited reduced tumor growth and enhanced immunity to infection. Flot2-null CD4+ T cells exhibited increased Th1 polarization, proliferation, Nur77 induction, and phosphorylation of ZAP70 and ERK1/2 upon weak TCR stimulation, indicating a sensitized TCR-triggering threshold. Single-cell RNA-Seq suggested that Flot2-null CD4+ T cells follow a similar route of activation as WT CD4+ T cells but exhibit higher occupancy of a discrete activation state under weak TCR stimulation. Given prior reports that TCR clustering influences sensitivity of T cells to stimuli, we evaluated TCR distribution with super-resolution microscopy. Flot2 ablation increased the number of surface TCR nanoclusters on naive CD4+ T cells. Collectively, we posit that Flot2 modulates T cell functionality to weak TCR stimulation, at least in part, by regulating surface TCR clustering. Our findings have implications for improving T cell reactivity in diseases with poor antigenicity, such as cancer and chronic infections.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LMAN1 serves as a cargo receptor for thrombopoietin. LMAN1 是血小板生成素的货物受体。

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-20 DOI: 10.1172/jci.insight.175704

Lesley A Everett, Zesen Lin, Ann Friedman, Vi T Tang, Greggory Myers, Ginette Balbin-Cuesta, Richard King, Guojing Zhu, Beth McGee, Rami Khoriaty

{"title":"LMAN1 serves as a cargo receptor for thrombopoietin.","authors":"Lesley A Everett, Zesen Lin, Ann Friedman, Vi T Tang, Greggory Myers, Ginette Balbin-Cuesta, Richard King, Guojing Zhu, Beth McGee, Rami Khoriaty","doi":"10.1172/jci.insight.175704","DOIUrl":"10.1172/jci.insight.175704","url":null,"abstract":"Thrombopoietin (TPO) is a plasma glycoprotein that binds its receptor on megakaryocytes (MKs) and MK progenitors, resulting in enhanced platelet production. The mechanism by which TPO is secreted from hepatocytes remains poorly understood. Lectin mannose-binding 1 (LMAN1) and multiple coagulation factor deficiency 2 (MCFD2) form a complex at the endoplasmic reticulum membrane, recruiting cargo proteins into COPII vesicles for secretion. In this study, we showed that LMAN1-deficient mice (with complete germline LMAN1 deficiency) exhibited mild thrombocytopenia, whereas the platelet count was entirely normal in mice with approximately 7% Lman1 expression. Surprisingly, mice deleted for Mcfd2 did not exhibit thrombocytopenia. Analysis of peripheral blood from LMAN1-deficient mice demonstrated normal platelet size and normal morphology of dense and alpha granules. LMAN1-deficient mice exhibited a trend toward reduced MK and MK progenitors in the bone marrow. We next showed that hepatocyte-specific but not hematopoietic Lman1 deletion results in thrombocytopenia, with plasma TPO level reduced in LMAN1-deficient mice, despite normal Tpo mRNA levels in LMAN1-deficient livers. TPO and LMAN1 interacted by coimmunoprecipitation in a heterologous cell line, and TPO accumulated intracellularly in LMAN1-deleted cells. Together, these studies verified the hepatocyte as the cell of origin for TPO production in vivo and were consistent with LMAN1 as the endoplasmic reticulum cargo receptor that mediates the efficient secretion of TPO. To our knowledge, TPO is the first example of an LMAN1-dependent cargo that is independent of MCFD2.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PCYT2 inhibits epithelial-mesenchymal transition in colorectal cancer by elevating YAP1 phosphorylation. PCYT2 通过提高 YAP1 磷酸化抑制结直肠癌上皮细胞向间质转化。

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-20 DOI: 10.1172/jci.insight.178823

Lian Zhou, Su Zhang, Lingli Wang, Xueqin Liu, Xuyang Yang, Lei Qiu, Ying Zhou, Qing Huang, Yang Meng, Xue Lei, Linda Wen, Junhong Han

{"title":"PCYT2 inhibits epithelial-mesenchymal transition in colorectal cancer by elevating YAP1 phosphorylation.","authors":"Lian Zhou, Su Zhang, Lingli Wang, Xueqin Liu, Xuyang Yang, Lei Qiu, Ying Zhou, Qing Huang, Yang Meng, Xue Lei, Linda Wen, Junhong Han","doi":"10.1172/jci.insight.178823","DOIUrl":"10.1172/jci.insight.178823","url":null,"abstract":"Metabolic reprogramming is a common feature in tumor progression and metastasis. Like proteins, lipids can transduce signals through lipid-protein interactions. During tumor initiation and metastasis, dysregulation of the Hippo pathway plays a critical role. Specifically, the inhibition of YAP1 phosphorylation leads to the relocation of YAP1 to the nucleus to activate transcription of genes involved in metastasis. Although recent studies reveal the involvement of phosphatidylethanolamine (PE) synthesis enzyme phosphoethanolamine cytidylyltransferase 2 (PCYT2) in tumor chemoresistance, the effect of PCYT2 on tumor metastasis remains elusive. Here, we show that PCYT2 was significantly downregulated in metastatic colorectal cancer (CRC) and acted as a tumor metastasis suppressor. Mechanistically, PCYT2 increased the interaction between PEBP1 and YAP1-phosphatase PPP2R1A, thus disrupting PPP2R1A-YAP1 association. As a result, phosphorylated YAP1 levels were increased, leading to YAP1 degradation through the ubiquitin protease pathway. YAP1 reduction in the nucleus repressed the transcription of ZEB1 and SNAIL2, eventually resulting in metastasis suppression. Our work provides insight into the role of PE synthesis in regulating metastasis and presents PCYT2 as a potential therapeutic target for CRC.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Talin1 dysfunction is genetically linked to systemic capillary leak syndrome.

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-20 DOI: 10.1172/jci.insight.173664

Naama Elefant, Georgia Rouni, Christina Arapatzi, Danit Oz-Levi, Racheli Sion-Sarid, William Js Edwards, Neil J Ball, Shira Yanovsky-Dagan, Alana R Cowell, Vardiella Meiner, Vladimir Vainstein, Sofia Grammenoudi, Doron Lancet, Benjamin T Goult, Tamar Harel, Vassiliki Kostourou

{"title":"Talin1 dysfunction is genetically linked to systemic capillary leak syndrome.","authors":"Naama Elefant, Georgia Rouni, Christina Arapatzi, Danit Oz-Levi, Racheli Sion-Sarid, William Js Edwards, Neil J Ball, Shira Yanovsky-Dagan, Alana R Cowell, Vardiella Meiner, Vladimir Vainstein, Sofia Grammenoudi, Doron Lancet, Benjamin T Goult, Tamar Harel, Vassiliki Kostourou","doi":"10.1172/jci.insight.173664","DOIUrl":"https://doi.org/10.1172/jci.insight.173664","url":null,"abstract":"Systemic capillary leak syndrome (SCLS) is a rare life-threatening disorder due to profound vascular leak. The trigger and the cause of the disease are currently unknown and there is no specific treatment. Here, we identified a rare heterozygous splice-site variant in the TLN1 gene in a familial SCLS case, suggestive of autosomal dominant inheritance with incomplete penetrance. Talin1 has a key role in cell adhesion by activating and linking integrins to the actin cytoskeleton. This variant causes in-frame skipping of exon 54 and is predicted to affect talin's C-terminal actin-binding site (ABS3). Modeling the SCLS-TLN1 variant in TLN1-heterozygous endothelial cells (ECs) disturbed the endothelial barrier function. Similarly, mimicking the predicted actin-binding disruption in TLN1-heterozygous ECs resulted in disorganized endothelial adherens junctions. Mechanistically, we established that the SCLS-TLN1 variant, through the disruption of talin's ABS3, sequestrates talin's interacting partner, vinculin, at cell-extracellular matrix adhesions, leading to destabilization of the endothelial barrier. We propose that pathogenic variants in TLN1 underlie SCLS, providing insight into the molecular mechanism of the disease that can be explored for future therapeutic interventions.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 24","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RTN1A mediates diabetes-induced AKI-to-CKD transition.

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-20 DOI: 10.1172/jci.insight.185826

Lulin Min, Ya Chen, Yixin Chen, Fang Zhong, Zhaohui Ni, Leyi Gu, Kyung Lee, John Cijiang He

{"title":"RTN1A mediates diabetes-induced AKI-to-CKD transition.","authors":"Lulin Min, Ya Chen, Yixin Chen, Fang Zhong, Zhaohui Ni, Leyi Gu, Kyung Lee, John Cijiang He","doi":"10.1172/jci.insight.185826","DOIUrl":"https://doi.org/10.1172/jci.insight.185826","url":null,"abstract":"Diabetic patients have increased susceptibility to acute kidney injury (AKI), and AKI could progress to chronic tubulointerstitial injury and fibrosis, referred to as AKI-to-chronic kidney disease (AKI-to-CKD) transition. However, whether diabetes directly promotes AKI-to-CKD transition is not known. We previously showed that reticulon-1A (RTN1A), a gene highly upregulated in injured renal tubular epithelial cells (RTECs), promotes AKI-to-CKD transition in nondiabetic settings. Therefore, we also examined whether reducing RTN1A expression could attenuate diabetes-induced AKI-to-CKD transition. Diabetes was induced by a high-fat diet and streptozotocin injections, and unilateral ischemic reperfusion injury was created as an AKI model in control, diabetic, and RTEC-specific Rtn1a-knockdown diabetic mice. AKI induced greater renal function decline, tubulointerstitial injury, and fibrosis in diabetic mice than in nondiabetic mice. Reduction of RTN1A markedly reduced the CKD development following AKI in diabetic mice, which was associated with reduced ER stress and mitochondrial dysfunction in RTECs. These findings indicate that diabetes markedly accelerates AKI-to-CKD transition and that RTN1A is a crucial mediator of diabetes-induced AKI-to-CKD transition. The development of RTN1A inhibitors could potentially attenuate AKI-to-CKD transition in diabetic patients.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 24","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gpnmb and Spp1 mark a conserved macrophage injury response masking fibrosis-specific programming in the lung. Gpnmb 和 Spp1 标志着一种保守的巨噬细胞损伤反应，掩盖了肺纤维化特异性程序。

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-20 DOI: 10.1172/jci.insight.182700

Emily M King, Yifan Zhao, Camille M Moore, Benjamin Steinhart, Kelsey C Anderson, Brian Vestal, Peter K Moore, Shannon A McManus, Christopher M Evans, Kara J Mould, Elizabeth F Redente, Alexandra L McCubbrey, William J Janssen

{"title":"Gpnmb and Spp1 mark a conserved macrophage injury response masking fibrosis-specific programming in the lung.","authors":"Emily M King, Yifan Zhao, Camille M Moore, Benjamin Steinhart, Kelsey C Anderson, Brian Vestal, Peter K Moore, Shannon A McManus, Christopher M Evans, Kara J Mould, Elizabeth F Redente, Alexandra L McCubbrey, William J Janssen","doi":"10.1172/jci.insight.182700","DOIUrl":"10.1172/jci.insight.182700","url":null,"abstract":"Macrophages are required for healthy repair of the lungs following injury, but they are also implicated in driving dysregulated repair with fibrosis. How these 2 distinct outcomes of lung injury are mediated by different macrophage subsets is unknown. To assess this, single-cell RNA-Seq was performed on lung macrophages isolated from mice treated with LPS or bleomycin. Macrophages were categorized based on anatomic location (airspace versus interstitium), developmental origin (embryonic versus recruited monocyte derived), time after inflammatory challenge, and injury model. Analysis of the integrated dataset revealed that macrophage subset clustering was driven by macrophage origin and tissue compartment rather than injury model. Gpnmb-expressing recruited macrophages that were enriched for genes typically associated with fibrosis were present in both injury models. Analogous GPNMB-expressing macrophages were identified in datasets from both fibrotic and nonfibrotic lung disease in humans. We conclude that this subset represents a conserved response to tissue injury and is not sufficient to drive fibrosis. Beyond this conserved response, we identified that recruited macrophages failed to gain resident-like programming during fibrotic repair. Overall, fibrotic versus nonfibrotic tissue repair is dictated by dynamic shifts in macrophage subset programming and persistence of recruited macrophages.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0