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1.
Ann Hematol ; 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38942949

RESUMO

Multiple myeloma (MM) is a form of clonal plasma cell malignancy that associates with clinical manifestations such as anemia, hypercalcemia, bone pain, and renal impairment. Approximately 20-50% of MM patients at initial diagnosis experience renal injury, a vital complication that significantly influences prognosis and quality of life. This review seeks to clarify the multifaceted mechanisms of renal injury in MM, scrutinizing the pathogenic role of monoclonal proteins, the impact of hypercalcemia, and direct renal infiltration by plasma cells. Furthermore, it evaluates current diagnostic approaches, reviews management strategies, and highlights potential avenues for future research. By incorporating the latest scientific evidence and insights, this article aims to provide a comprehensive understanding of MM-associated renal impairment, offering a valuable resource for researchers and clinicians in handling this complex complication.

2.
J Transl Med ; 21(1): 323, 2023 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-37179292

RESUMO

BACKGROUND: Pericyte-myofibroblast transition (PMT) has been confirmed to contribute to renal fibrosis in several kidney diseases, and transforming growth factor-ß1 (TGF-ß1) 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. PDGFRß + pericytes were isolated using MACS, and an in vitro model of PMT was induced by 5 ng/ml TGF-ß1. 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-ß1 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-ß1-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.


Assuntos
Transdução de Sinais , Fator de Crescimento Transformador beta1 , Fator de Crescimento Transformador beta1/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Hexoquinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Pericitos/metabolismo , Miofibroblastos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Sirolimo , Glicólise
3.
Kidney Int ; 93(6): 1384-1396, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29571940

RESUMO

Ultrafiltration failure is a major complication of long-term peritoneal dialysis, resulting in dialysis failure. Peritoneal fibrosis induced by continuous exposure to high glucose dialysate is the major contributor of ultrafiltration failure, for which there is no effective treatment. Overactivation of several signaling pathways, including transforming growth factor-ß1 (TGF-ß1) and platelet-derived growth factor (PDGF) pathways, contribute to the development of peritoneal fibrosis. Therefore, simultaneously blocking multiple signaling pathways might be a potential novel method of treating peritoneal fibrosis. Previously, we showed that core fucosylation, an important posttranslational modification of the TGF-ß1 receptors, can regulate the activation of TGF-ß1 signaling in renal interstitial fibrosis. However, it remains unclear whether core fucosylation affects the progression of peritoneal fibrosis. Herein, we show that core fucosylation was enriched in the peritoneal membrane of rats accompanied by peritoneal fibrosis induced by a high glucose dialysate. Blocking core fucosylation dramatically attenuated peritoneal fibrosis in the rat model achieved by simultaneously inactivating the TGF-ß1 and PDGF signaling pathways. Next the protective effects of blocking core fucosylation and imatinib (a selective PDGF receptor inhibitor) on peritoneal fibrosis were compared and found to exhibit a greater inhibitory effect over imatinib alone, suggesting that blocking activation of multiple signaling pathways may have superior inhibitory effects on the development of peritoneal fibrosis. Thus, core fucosylation is essential for the development of peritoneal fibrosis by regulating the activation of multiple signaling pathways. This may be a potential novel target for drug development to treat peritoneal fibrosis.


Assuntos
Soluções para Diálise , Fucose/metabolismo , Fucosiltransferases/metabolismo , Glucose , Diálise Peritoneal/métodos , Fibrose Peritoneal/prevenção & controle , Peritônio/metabolismo , Interferência de RNA , Animais , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fucosiltransferases/genética , Mesilato de Imatinib/farmacologia , Masculino , Fibrose Peritoneal/induzido quimicamente , Fibrose Peritoneal/metabolismo , Fibrose Peritoneal/patologia , Peritônio/efeitos dos fármacos , Peritônio/patologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo
4.
Int Urol Nephrol ; 56(1): 303-311, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37355515

RESUMO

PURPOSE: Disturbance in metabolism and inflammation are the main causes of kidney injury in patients with late stage diabetic nephropathy (DN). Here, we explored whether autophagy was activated in mice with late stage DN and whether it was associated with disturbance in metabolism and inflammation. METHODS: In total, mice were divided into the control group (db/m) and DN group (db/db). Mice were raised for 7 months, and their biochemical indices were measured. Subsequently, their kidneys were collected to detect autophagy and the related nutrient-sensing and inflammatory signaling pathways in late stage DN. RESULTS: The expression levels of autophagy markers LC3-I and LC3-II were significantly increased in mice with late stage DN, whereas that of autophagy flux marker P62 was significantly decreased, indicating activation of autophagy. Concurrently, mechanistic target of rapamycin was highly expressed as a cellular nutrient-sensing and energy regulator in mice with late stage DN. Additionally, the expression levels of markers of nutrient-sensing signaling pathways adenosine monophosphate-activated protein kinase (AMPK) were increased markedly in mice with late stage DN. Additionally, the expression levels of the marker of nutrient-sensing signaling pathways silent information regulator T1 (SIRT1), the marker of inflammatory signaling pathways high mobility group box protein 1 (HMGB1), and interferon regulatory factor 3 (IRF3) were significantly increased in mice with late stage DN. CONCLUSIONS: The findings of our study indicate that autophagy activation in late stage DN may interfere with nutrient-sensing and inflammatory signaling pathways involving AMPK, SIRT1, HMGB1, and IRF3.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Proteína HMGB1 , Humanos , Camundongos , Animais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Sirtuína 1/metabolismo , Rim/metabolismo , Transdução de Sinais , Autofagia , Inflamação/complicações , Nutrientes
5.
Medicine (Baltimore) ; 103(19): e38103, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38728448

RESUMO

RATIONALE: Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy caused by reduced activity of the von Willebrand factor-cleaving protease (ADAMTS13), which can be life-threatening. The patient reported in this case study also had concurrent Sjögren syndrome and renal impairment, presenting multiple symptoms and posing a great challenge in treatment. PATIENT CONCERNS: A 25-year-old woman in the postpartum period visited the hospital due to indifference in consciousness for more than 1 day following cesarean section 8 days prior. DIAGNOSIS: Notable decreases were observed in platelets, hemoglobin, creatinine, and ADAMTS13 levels. After a consultative examination by an ophthalmologist, she was diagnosed with retinal hemorrhage in the right eye and dry eye syndrome in both eyes. INTERVENTIONS: Having been diagnosed with TTP with Sjögren syndrome and renal impairment, she received repeated treatments with plasmapheresis combined with rituximab. OUTCOMES: Following treatment and during the follow-up period, the patient's platelet counts and bleeding symptoms significantly improved. LESSONS: TTP has a high mortality rate, and when combined with Sjögren syndrome and renal impairment, it poses an even greater challenge in treatment. However, after administering standard plasmapheresis combined with rituximab treatment, the treatment outcome is favorable.


Assuntos
Plasmaferese , Púrpura Trombocitopênica Trombótica , Rituximab , Síndrome de Sjogren , Humanos , Feminino , Síndrome de Sjogren/complicações , Síndrome de Sjogren/terapia , Plasmaferese/métodos , Adulto , Púrpura Trombocitopênica Trombótica/terapia , Púrpura Trombocitopênica Trombótica/complicações , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Rituximab/uso terapêutico , Rituximab/administração & dosagem , Terapia Combinada , Insuficiência Renal/terapia , Insuficiência Renal/etiologia , Fatores Imunológicos/uso terapêutico , Fatores Imunológicos/administração & dosagem
6.
JCI Insight ; 9(9)2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38716725

RESUMO

IgA nephropathy (IgAN) represents the main cause of renal failure, while the precise pathogenetic mechanisms have not been fully determined. Herein, we conducted a cross-species single-cell survey on human IgAN and mouse and rat IgAN models to explore the pathogenic programs. Cross-species single-cell RNA sequencing (scRNA-Seq) revealed that the IgAN mesangial cells (MCs) expressed high levels of inflammatory signatures CXCL12, CCL2, CSF1, and IL-34 and specifically interacted with IgAN macrophages via the CXCL12/CXCR4, CSF1/IL-34/CSF1 receptor, and integrin subunit alpha X/integrin subunit alpha M/complement C3 (C3) axes. IgAN macrophages expressed high levels of CXCR4, PDGFB, triggering receptor expressed on myeloid cells 2, TNF, and C3, and the trajectory analysis suggested that these cells derived from the differentiation of infiltrating blood monocytes. Additionally, protein profiling of 21 progression and 28 nonprogression IgAN samples revealed that proteins CXCL12, C3, mannose receptor C-type 1, and CD163 were negatively correlated with estimated glomerular filtration rate (eGFR) value and poor prognosis (30% eGFR as composite end point). Last, a functional experiment revealed that specific blockade of the Cxcl12/Cxcr4 pathway substantially attenuated the glomerulus and tubule inflammatory injury, fibrosis, and renal function decline in the mouse IgAN model. This study provides insights into IgAN progression and may aid in the refinement of IgAN diagnosis and the optimization of treatment strategies.


Assuntos
Progressão da Doença , Glomerulonefrite por IGA , Macrófagos , Análise de Célula Única , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Ratos , Quimiocina CXCL12/metabolismo , Modelos Animais de Doenças , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/patologia , Interleucinas , Macrófagos/imunologia , Macrófagos/metabolismo , Células Mesangiais/patologia , Células Mesangiais/metabolismo , Células Mesangiais/imunologia , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Ratos Wistar
7.
Biomed Pharmacother ; 175: 116636, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38677245

RESUMO

PURPOSE: Renal interstitial fibrosis is a pathological manifestation of the progression of diabetic kidney disease (DKD). Dendrobium officinale polysaccharides (DOP), one of the major active components of Dendrobium officinale, have hypoglycemic and hypolipidemic effects and are used clinically to treat diabetes. However, the role of DOP in delaying DKD progression remains unclear. This study aimed to explore the potential mechanisms by which DOP delays DKD renal interstitial fibrosis. METHODS: Using db/db mice as a model of DKD, we administered DOP by gavage and observed its therapeutic effectiveness. Employing ASO technology, we knocked down lncRNA XIST expression in kidney tissues and detected the expression of lncRNA XIST, TGF-ß1, and renal interstitial fibrosis-related molecules. RESULTS: DOP was primarily composed of monosaccharides, with 91.57% glucose and 1.41% mannose, forming a spheroid-like structure. It has a high polydispersity index with an Mw/Mn of 6.146, and the polysaccharides are mainly connected by 4-Man(p) and 4-Glc(p) linkages. In the kidneys of db/db mice, lncRNA XIST and TGF-ß1 are highly expressed; however, their expression is significantly reduced after gastric infusion with DOP, and upon knockdown of lncRNA XIST, it might delay the progression of renal interstitial fibrosis in DKD. CONCLUSION: DOP may delay the progression of DKD renal interstitial fibrosis through the regulation of the LncRNA XIST/TGF-ß1 related fibrotic pathway. This provides a new perspective for clinical strategies to delay the progression of DKD renal interstitial fibrosis.


Assuntos
Dendrobium , Nefropatias Diabéticas , Fibrose , Camundongos Endogâmicos C57BL , Polissacarídeos , RNA Longo não Codificante , Fator de Crescimento Transformador beta1 , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , Dendrobium/química , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/genética , Polissacarídeos/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Masculino , Camundongos , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismo
8.
Heliyon ; 9(5): e15684, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37144201

RESUMO

Dysfunction of B-cell subsets is critical in the development of systemic lupus erythematosus (SLE). There is a great diversity of B-lineage cells, and their features and functions in SLE need to be clarified. In this study, we analyzed single-cell RNA sequencing (scRNA-seq) data from peripheral blood mononuclear cells (PBMCs) and bulk transcriptomic data of isolated B-cell subsets from patients with SLE and healthy controls (HCs). We preformed scRNA-seq analysis focused on the diversity of B-cell subsets and identified a subset of antigen-presenting B cells in SLE patients that highly expressed ITGAX. A list of marker genes of each B-cell subset in patients with SLE was also identified. Comparison of bulk transcriptomic data of isolated B-cell subpopulations between SLE patients and HCs revealed the upregulated differentially expressed genes (DEGs) for each B-cell subpopulation in SLE. Common genes identified using these two methods were considered to be upregulated marker genes of B cells in SLE. The scRNA-seq data of SLE patients and HCs revealed that CD70 and LY9 were overexpressed in B cells vs. other cell types from SLE patients, and this pattern was validated by RT‒qPCR. Because CD70 is the cellular ligand of CD27, previous studies on CD70 have focused mainly on T cells from SLE patients. LY9 appears to have different functions in mice and humans: its expression is decreased in lupus-prone mice but is increased in T cells and some B-cell subpopulations in SLE patients. Here, we describe the overexpression of two costimulatory molecules, CD70 and LY9, which may be a novel feature of B cells in SLE patients.

9.
J Ethnopharmacol ; 313: 116601, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37146843

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fibrosis is a fundamental change occurring in impaired renal function and plays an important role in the progression of diabetic kidney disease (DKD). Dendrobium officinale Kimura & Migo polysaccharide (DOP), a primary active component of Dendrobium officinale Kimura & Migo, is reported to act on reducing blood glucose, suppressing inflammation. However, the anti-fibrosis effect of DOP in the treatment of DKD is still unclear. AIM OF THE STUDY: To explore the therapeutic effect of DOP on renal fibrosis in DKD. MATERIALS AND METHODS: We used db/db mice as a DKD model and administered DOP by oral gavage. The expression of miRNA-34a-5p, SIRT1, and fibrosis molecules (TGF-ß, CTGF, and a-SMA) were detected in renal tissue. Human renal tubular epithelium cells (HK-2) were cultured with 5.5 mM glucose (LG) or 25 mM glucose (HG), and intervened with 100-400 µg/ml DOP. The changes of the above indicators were observed in vitro. RESULTS: MiRNA-34a-5p was mainly localised in the nucleus and increased expression in the DKD mice. Inhibition or excitation of miRNA-34a-5p is involved in renal fibrosis by regulating SIRT1. DOP could depress the miRNA-34a-5p/SIRT1 signalling pathway to relieve renal fibrosis. Moreover, DOP has outstanding results in the treatment of DKD through hypoglycaemic action and weight reduction. CONCLUSIONS: DOP plays a protective role in arresting or slowing the progression of fibrosis, which may provide a novel clinical treatment strategy for DKD.


Assuntos
Dendrobium , Hiperglicemia , MicroRNAs , Humanos , Animais , Camundongos , Hiperglicemia/tratamento farmacológico , Sirtuína 1/metabolismo , Fibrose , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Glucose , MicroRNAs/genética , MicroRNAs/metabolismo , Rim/metabolismo
10.
Front Immunol ; 14: 1282890, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38053999

RESUMO

Changes in lifestyle induce an increase in patients with hyperuricemia (HUA), leading to gout, gouty arthritis, renal damage, and cardiovascular injury. There is a strong inflammatory response in the process of HUA, while dysregulation of immune cells, including monocytes, macrophages, and T cells, plays a crucial role in the inflammatory response. Recent studies have indicated that urate has a direct impact on immune cell populations, changes in cytokine expression, modifications in chemotaxis and differentiation, and the provocation of immune cells by intrinsic cells to cause the aforementioned conditions. Here we conducted a detailed review of the relationship among uric acid, immune response, and inflammatory status in hyperuricemia and its complications, providing new therapeutic targets and strategies.


Assuntos
Artrite Gotosa , Gota , Hiperuricemia , Humanos , Hiperuricemia/complicações , Hiperuricemia/metabolismo , Ácido Úrico/metabolismo , Gota/tratamento farmacológico , Artrite Gotosa/tratamento farmacológico , Inflamação/complicações
11.
Sci Rep ; 12(1): 11147, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35778423

RESUMO

Kidney functions, including electrolyte and water reabsorption and secretion, could be influenced by circulating hormones. The pituitary gland produces a variety of hormones and cytokines; however, the influence of these factors on the kidney has not been well explained and explored. To provide more in-depth information and insights to support the pituitary-kidney axis connection, we used mouse pituitary and kidney single-cell transcriptomics data from the GEO database for further analysis. Based on a ligand-receptor pair analysis, cell-cell interaction patterns between the pituitary and kidney cell types were described. Key ligand-receptor pairs, such as GH-GHR, PTN-SDC2, PTN-SDC4, and DLK1-NOTCH3, were relatively active in the pituitary-kidney axis. These ligand-receptor pairs mainly target proximal tubule cells, principal cells, the loop of Henle, intercalated cells, pericytes, mesangial cells, and fibroblasts, and these cells are related to physiological processes, such as substance reabsorption, angiogenesis, and tissue repair. Our results suggested that the pituitary gland might directly regulate kidney function by secreting multiple hormones or cytokines and indicated that the above ligand-receptor pairs might represent a new research focus for studies on kidney function or kidney disease.


Assuntos
Análise de Dados , Hipófise , Animais , Comunicação Celular/genética , Citocinas/metabolismo , Hormônios/metabolismo , Rim/metabolismo , Ligantes , Camundongos , Hipófise/metabolismo , Análise de Sequência de RNA
12.
Biomed Pharmacother ; 153: 113433, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076550

RESUMO

BACKGROUND: Lupus nephritis (LN) is the most common complication of systemic lupus erythematosus (SLE), and the abnormal activation of the alternative complement pathway is associated with the pathogenesis of LN. As an inhibitor of complement factor B (CFB) in the alternative pathway, LNP023 has been used in the treatment of a variety of renal diseases with abnormal complement system involvement, such as paroxysmal nocturnal hemoglobinuria, IgA nephropathy, and membranous nephropathy. The aim of our study was to explore whether LNP023 improved LN in MRL/lpr mice by inhibiting the activation of the alternative complement pathway. METHODS: The mice were divided into a normal control group (Normal group) (n = 6), MRL/lpr model group (n = 6), and LNP023 group (n = 6). The LNP023 group was administered LNP023 for 2 weeks by gavage; the MRL/lpr model group was administered saline for 2 weeks by gavage; and the Normal group was administered saline for 2 weeks by gavage. External signs, renal pathology, renal function, renal immune complex and complement deposition, serum anti-dsDNA, serum ANA concentration, and the expression of core complement factors in the alternative complement pathway were analyzed in the 3 groups of animals. The core targets of LNP023 in the treatment of LN were screened using network pharmacology. The pathogenicity of the core targets in LN was verified by analyzing the mRNA expression of the core targets in the peripheral blood mononuclear cells (PBMCs) of normal individuals, SLE patients, and LN patients. The mRNA and protein expression of core targets in the Normal group, MRL/lpr group, and LNP023 group were analyzed to verify whether LNP023 exerted it LN therapeutic effect through the regulation of core targets. RESULTS: Compared with the MRL/lpr group, the LNP023 group had reduced lupus-like signs, improved renal function, decreased serum anti-dsDNA and ANA concentrations, and reduced renal IgM, IgG, IgG1, C1q, C3, and C4 deposition. Renal pathology showed that LNP023 attenuated pathological damage in the kidneys of MRL/lpr mice. Compared with the MRL/lpr model group, the treatment group had no crescent formation, less immune deposition, no nuclear fragmentation, and less inflammatory cell infiltration. The expression of complement proteins C3, C3b, CR1, CFB, and C5b-9 in kidney tissues and liver was decreased, and the expression of C5 was increased. Network pharmacology screening indicated that AKT, TNF-α, MDM2, UBC, STST3, ESR1, and TP53 were core targets of LNP023 in the treatment of LN. Compared with that in the Normal group, the mRNA expression of the core target in the SLE and LN groups was different; compared with the MRL/lpr group, the LNP023 treatment group showed different mRNA and protein expression levels of AKT, TNF-α, and STST3. CONCLUSION: LNP023 improves LN in MRL/lpr mice. The mechanism is as follows: LNP023 binds to CFB to inhibit the activation of the alternative complement pathway. LNP023 treatment for LN may also play a role in regulating the protein expression of AKT, TNF-α, and STST3.


Assuntos
Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Animais , Fator B do Complemento/antagonistas & inibidores , Fatores Imunológicos/farmacologia , Rim , Leucócitos Mononucleares/patologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Proteínas Proto-Oncogênicas c-akt , RNA Mensageiro/uso terapêutico , Fator de Necrose Tumoral alfa/farmacologia
13.
Front Med (Lausanne) ; 9: 898624, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35755045

RESUMO

Background: The Chinese herbal formula Shenyi (SY) is a prescription that was developed by the Department of Nephrology, Chinese People's Liberation Army General Hospital. This preparation is mainly used to treat chronic kidney disease (CKD) caused by Diabetic nephropathy (DN) and is effective. However, the active ingredients of SY, DN treatment-related molecular targets and the effector mechanisms are still unclear. Methods: The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and the Traditional Chinese Medicine and Chemical Component Database of Shanghai Institute of Organic Chemistry were used to screen the active ingredients in SY, the TCMSP database and Swiss Target Prediction database were used to collect the targets of the active ingredients of SY, and the Gene Cards and Online Mendelian Inheritance in Man (OMIM) databases were used to screen for DN pathogenesis targets. The intersections of the component targets and disease targets were mapped to obtain the therapeutic targets. The METASCAPE database was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the therapeutic targets. Cytoscape 3.7.2 was used to analyze topological parameters and construct a network of SY for the treatment of DN. Results: Sixty-two active ingredients and 497 active ingredient effector targets in SY, 3260 DN-related targets, and 271 SY treatments for DN targets were identified. Among these targets, 17 were core targets, including AKT1, tumor necrosis factor (TNF), interleukin-6 (IL6), and TP53. The GO and KEGG enrichment analyses show that SY's therapeutic effects for DN occur mainly through pathways such as advanced glycation end product (AGE)-RAGE, PI3K-Akt, and IL-17. Conclusion: Multiple active ingredients in SY exhibit treatment effects on DN by affecting metabolism, inhibiting inflammation, and affecting cell structure growth.

14.
Front Immunol ; 13: 857025, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35603220

RESUMO

Background: Understanding the acute kidney injury (AKI) microenvironment changes and the complex cellular interaction is essential to elucidate the mechanisms and develop new targeted therapies for AKI. Methods: We employed unbiased single-cell RNA sequencing to systematically resolve the cellular atlas of kidney tissue samples from mice at 1, 2 and 3 days after ischemia-reperfusion AKI and healthy control. The single-cell transcriptome findings were validated using multiplex immunostaining, western blotting, and functional experiments. Results: We constructed a systematic single-cell transcriptome atlas covering different AKI timepoints with immune cell infiltration increasing with AKI progression. Three new proximal tubule cells (PTCs) subtypes (PTC-S1-new/PTC-S2-new/PTC-S3-new) were identified, with upregulation of injury and repair-regulated signatures such as Sox9, Vcam1, Egr1, and Klf6 while with downregulation of metabolism. PTC-S1-new exhibited pro-inflammatory and pro-fibrotic signature compared to normal PTC, and trajectory analysis revealed that proliferating PTCs were the precursor cell of PTC-S1-new, and part of PTC-S1-new cells may turn into PTC-injured and then become fibrotic. Cellular interaction analysis revealed that PTC-S1-new and PTC-injured interacted closely with infiltrating immune cells through CXCL and TNF signaling pathways. Immunostaining validated that injured PTCs expressed a high level of TNFRSF1A and Kim-1, and functional experiments revealed that the exogenous addition of TNF-α promoted kidney inflammation, dramatic injury, and specific depletion of TNFRSF1A would abrogate the injury. Conclusions: The single-cell profiling of AKI microenvironment provides new insight for the deep understanding of molecular changes of AKI, and elucidates the mechanisms and developing new targeted therapies for AKI.


Assuntos
Injúria Renal Aguda , Traumatismo por Reperfusão , Injúria Renal Aguda/metabolismo , Animais , Células Epiteliais/metabolismo , Fibrose , Túbulos Renais Proximais/patologia , Camundongos , Traumatismo por Reperfusão/patologia
15.
Acta Biomater ; 142: 99-112, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35189379

RESUMO

Proteinuria is a clinical manifestation of chronic kidney disease that aggravates renal interstitial fibrosis (RIF), in which injury of peritubular microvessels is an important event. However, the changes in peritubular microvessels induced by proteinuria and their molecular mechanisms remain unclear. Thus, we aimed to develop a co-culture microfluidic device that contains renal tubules and peritubular microvessels to create a proteinuria model. We found that protein overload in the renal tubule induced trans-differentiation and apoptosis of endothelial cells (ECs) and pericytes. Moreover, profiling of secreted proteins in this model revealed that a paracrine network between tubules and microvessels was activated in proteinuria-induced microvascular injury. Multiple cytokine receptors in this paracrine network were core-fucosylated. Inhibition of core fucosylation significantly reduced ligand-receptor binding ability and blocked downstream pathways, alleviating trans-differentiation and apoptosis of ECs and pericytes. Furthermore, the protective effect of genetic FUT8 deficiency on proteinuria overload-induced RIF and pericyte-myofibroblast trans-differentiation was validated in FUT8 knockout heterozygous mice. In conclusion, we constructed and used a multiple-unit integrated microfluidic device to uncover the mechanism of proteinuria-induced RIF. Furthermore, FUT8 may serve as a hub-like therapeutic target to alleviate peritubular microvascular injury in RIF. STATEMENT OF SIGNIFICANCE: In this study, we constructed a multiple-unit integrated renal tubule-vascular chip. We reproduced human proteinuria on the chip and found that multiple receptors were modified by FUT8-catalyzed core fucosylation (CF) involved in the cross-talk between renal tubules and peritubular microvessels in proteinuria-induced RIF, and inhibiting the FUT8 of receptors could block the tubule-microvessel paracrine network and reverse the damage of peritubular microvessels and renal interstitial fibrosis. This tubule-vascular chip may provide a prospective platform to facilitate future investigations into the mechanisms of kidney diseases, and target-FUT8 inhibition may be an innovative and potential therapeutic strategy for RIF induced by proteinuria.


Assuntos
Nefropatias , Microfluídica , Animais , Células Endoteliais/metabolismo , Feminino , Fibrose , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Humanos , Nefropatias/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteinúria
16.
Front Immunol ; 13: 908851, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36275661

RESUMO

Background: Lupus nephritis (LN) is one of the most common and serious complications of systemic lupus erythaematosus (SLE). Genetic factors play important roles in the pathogenesis of LN and could be used to predict who might develop LN. The purpose of this study was to screen for susceptible candidates of LN across the whole genome in the Han Chinese population. Methods: 592 LN patients and 453 SLE patients without renal damage were genotyped at 492,970 single nucleotide polymorphisms (SNPs) in the genome-wide association study (GWAS). Fifty-six SNPs were selected for replication in an independent cohort of 188 LN and 171 SLE without LN patients. Further quantitative real-time (qRT) PCR was carried out in 6 LN patients and 6 healthy controls. Gene-based analysis was conducted using the versatile gene-based test for GWAS. Subsequently, enrichment and pathway analyses were performed in the DAVID database. Results: The GWAS analysis and the following replication research identified 9 SNPs showing suggestive correlation with LN (P<10-4). The most significant SNP was rs12606116 (18p11.32), at P=8.72×10-6. The qRT-PCR results verified the mRNA levels of LINC00470 and ADCYAP1, the closest genes to rs12606116, were significantly lower in LN patients. From the gene-based analysis, 690 genes had suggestive evidence of association (P<0.05), including LINC00470. The enrichment analysis identified the involvement of transforming growth factor beta (TGF-ß) signalings in the development of LN. Lower plasma level of TGF-ß1 (P<0.05) in LN patients and lower expression of transforming growth factor beta receptor 2 in lupus mice kidney (P<0.05) futher indicate the involvement of TGF-ß in LN. Conclusions: Our analyses identified several promising susceptibility candidates involved in LN, and further verification of these candidates was necessary.


Assuntos
Nefrite Lúpica , Animais , Camundongos , Nefrite Lúpica/genética , Polimorfismo de Nucleotídeo Único , Estudo de Associação Genômica Ampla , Fator de Crescimento Transformador beta1/genética , RNA Mensageiro , China , Receptores de Fatores de Crescimento Transformadores beta/genética
17.
EBioMedicine ; 70: 103477, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34284174

RESUMO

BACKGROUND: Type I interferon signature is one of the most important features of systemic lupus erythematosus (SLE), which indicates an active immune response to antigen invasion. Characteristics of type I interferon-stimulated genes (ISGs) in SLE patients have not been well described thus far. METHODS: We analyzed 35,842 cells of PBMC single-cell RNA sequencing data of five SLE patients and three healthy controls. Thereafter, 178 type I ISGs among DEGs of all cell clusters were screened based on the Interferome Database and AUCell package was used for ISGs activity calculation. To determine whether common ISG features exist in PBMCs and kidneys of patients with SLE, we analyzed kidney transcriptomic data from patients with lupus nephritis (LN) from the GEO database. MRL/lpr mice model were used to verify our findings. FINDINGS: We found that monocytes, B cells, dendritic cells, and granulocytes were significantly increased in SLE patients, while subsets of T cells were significantly decreased. Neutrophils and low-density granulocytes (LDGs) exhibited the highest ISG activity. GO and pathway enrichment analyses showed that DEGs focused on leukocyte activation, cell secretion, and pathogen infection. Thirty-one common ISGs were found expressed in both PBMCs and kidneys; these ISGs were also most active in neutrophils and LDGs. Transcription factors including PLSCR1, TCF4, IRF9 and STAT1 were found to be associated to ISGs expression. Consistently, we found granulocyte infiltration in the kidneys of MRL/lpr mice. Granulocyte inhibitor Avacopan reduced granulocyte infiltration and reversed renal conditions in MRL/lpr mice. INTERPRETATION: This study shows for the first time, the use of the AUCell method to describe ISG activity of granulocytes in SLE patients. Moreover, Avacopan may serve as a granulocyte inhibitor for treatment of lupus patients in the future. FUNDING: None.


Assuntos
Interferons/metabolismo , Lúpus Eritematoso Sistêmico/genética , Transcriptoma , Animais , Feminino , Humanos , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/genética , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/metabolismo , Rim/metabolismo , Rim/patologia , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Transferência de Fosfolipídeos/genética , Proteínas de Transferência de Fosfolipídeos/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição 4/genética , Fator de Transcrição 4/metabolismo
18.
Cell Rep ; 33(12): 108525, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33357427

RESUMO

IgA nephropathy (IgAN) is the leading cause of kidney failure due to an incomplete understanding of its pathogenesis. We perform single-cell RNA sequencing (RNA-seq) on kidneys and CD14+ peripheral blood mononuclear cells (PBMCs) collected from IgAN and normal samples. In IgAN, upregulation of JCHAIN in mesangial cells provides insight into the trigger mechanism for the dimerization and deposition of IgA1 in situ. The pathological mesangium also demonstrates a prominent inflammatory signature and increased cell-cell communication with other renal parenchymal cells and immune cells, suggesting disease progress from the mesangium to the entire kidney. Specific gene expression of kidney-resident macrophages and CD8+ T cells further indicates abnormal regulation associated with proliferation and inflammation. A transitional cell type among intercalated cells with fibrosis signatures is identified, suggesting an adverse outcome of interstitial fibrosis. Altogether, we systematically analyze the molecular events in the onset and progression of IgAN, providing a promising landscape for disease treatment.


Assuntos
Glomerulonefrite por IGA/imunologia , Rim/patologia , Transcriptoma/genética , Células Cultivadas , Progressão da Doença , Humanos
19.
Sci Rep ; 7(1): 16914, 2017 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-29209018

RESUMO

Pericytes have been identified as a major source of myofibroblasts in renal interstitial fibrosis (RIF). The overactivation of several signaling pathways, mainly the TGF-ß and PDGF pathways, initiates the pericyte-myofibroblast transition during RIF. Key receptors in these two pathways have been shown to be modified by fucosyltransferase 8 (FUT8), the enzyme that catalyzes core fucosylation. This study postulated that core fucosylation might play an important role in regulating the pericyte transition in RIF. The data showed that core fucosylation increased with the extent of RIF in patients with IgA nephropathy (IgAN). Similarly, core fucosylation of pericytes increased in both a unilateral ureteral occlusion (UUO) mouse model and an in vitro model of pericyte transition. Inhibition of core fucosylation by adenoviral-mediated FUT8 shRNA in vivo and FUT8 siRNA in vitro significantly reduced pericyte transition and RIF. In addition, the activation of both the TGF-ß/Smad and PDGF/ERK pathways was blocked by core fucosylation inhibition. In conclusion, core fucosylation may regulate the pericyte transition in RIF by modifying both the TGF-ß/Smad and PDGF/ERK pathways. Glycosylation might be a novel "hub" target to prevent RIF.


Assuntos
Fibrose/metabolismo , Rim/patologia , Miofibroblastos/patologia , Pericitos/metabolismo , Adulto , Animais , Modelos Animais de Doenças , Feminino , Fibrose/patologia , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Glomerulonefrite por IGA/patologia , Glicosilação , Humanos , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miofibroblastos/metabolismo , Pericitos/patologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo
20.
Chin Med J (Engl) ; 130(18): 2147-2155, 2017 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-28875950

RESUMO

BACKGROUND:: Core fucosylation (CF), catalyzed by α-1,6 fucosyltransferase (Fut8) in mammals, plays an important role in pathological processes through posttranslational modification of key signaling receptor proteins, including transforming growth factor (TGF)-ß receptors and platelet-derived growth factor (PDGF) receptors. However, its effect on peritoneal fibrosis is unknown. Here, we investigated its influence on epithelial-mesenchymal transition (EMT) of rat peritoneal mesothelial cells (PMCs) in vitro induced by a high-glucose (HG) culture solution. METHODS:: Rat PMCs were first cultured in a HG (2.5%) culture solution to observe the CF expression level (fluorescein isothiocyanate-lens culinaris agglutinin), we next established a knockdown model of rat PMCs in vitro with Fut8 small interfering RNA (siRNA) to observe whether inhibiting CF decreases the messenger RNA (mRNA) expression and protein expression of Fut8 and reverses EMT status. Rat PMCs were randomly divided into control group, mock group (transfected with scrambled siRNA), Fut8 siRNA group, HG group, HG + mock group, and HG + Fut8 siRNA group. Finally, we examined the activation of TGF-ß/Smad2/3 signaling and PDGF/extracellular signal-regulated kinase (ERK) signaling to observe the influence of CF on them. RESULTS:: CF, Fut8 mRNA, and protein expression were all significantly upregulated in HG- induced EMT model than those in the control rat PMCs (P < 0.05). Fut8 siRNA successfully blocked CF of TGF-ß receptors and PDGF receptors and attenuated the EMT status (E-cadherin and α-SMA and phenotypic changes) in HG-induced rat PMCs. In TGF-ß/Smad2/3 signaling, Fut8 siRNA did not suppress the protein expression of TGF-ß receptors and Smad2/3; however, it significantly suppressed the phosphorylation of Smad2/3 (relative expression folds of HG + Fut8 group vs. HG group: 7.6 ± 0.4 vs. 15.1 ± 0.6, respectively, P < 0.05). In PDGF/ERK signaling, Fut8 siRNA did not suppress the protein expression of PDGF receptors and ERK, but it significantly suppressed the phosphorylation of ERK (relative expression folds of HG + Fut8 group vs. HG group: 8.7 ± 0.9 vs. 15.6 ± 1.2, respectively, P < 0.05). Blocking CF inactivated the activities of TGF-ß and PDGF signaling pathways, and subsequently blocked EMT. CONCLUSIONS:: These results demonstrate that CF contributes to rat PMC EMT, and that blocking it attenuates EMT. CF regulation is a potential therapeutic target of peritoneal fibrosis.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Fibrose Peritoneal/metabolismo , Animais , Western Blotting , Transição Epitelial-Mesenquimal/genética , Epitélio/metabolismo , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Imunoprecipitação , Fibrose Peritoneal/genética , Fosforilação , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Distribuição Aleatória , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo
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