RESUMO
Renal fibrosis is a characteristic hallmark of chronic kidney disease (CKD) that ultimately results in renal failure, leaving patients with few therapeutic options. TGF-ß is a master regulator of renal fibrosis and mediates progressive renal fibrosis via both canonical and noncanonical signaling pathways. In the canonical Smad signaling, Smad3 is a key mediator in tissue fibrosis and mediates renal fibrosis via a number of noncoding RNAs (ncRNAs). In this regard, targeting Smad3-dependent ncRNAs may offer a specific therapy for renal fibrosis. This review highlights the significance and innovation of TGF-ß/Smad3-associated ncRNAs as biomarkers and therapeutic targets in renal fibrogenesis. In addition, the underlying mechanisms of these ncRNAs and their future perspectives in the treatment of renal fibrosis are discussed.
Assuntos
Rim , Insuficiência Renal Crônica , Humanos , Fibrose , Rim/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
The Hippo/YAP pathway plays a critical role in tissue homeostasis. Our previous work demonstrated that renal tubular YAP activation induced by double knockout (dKO) of the upstream Hippo kinases Mst1 and Mst2 promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious pathways are simultaneously activated. Here, we show that tubular YAP was already activated 6 h after unilateral ureteral obstruction (UUO). Tubular YAP deficiency greatly attenuated tubular cell overproliferation, tubular injury, and renal inflammation induced by UUO or cisplatin. YAP promoted the transcription of the transcription factor KLF5. Consistent with this, the elevated expression of KLF5 and its target genes in Mst1/2 dKO or UUO kidneys was blocked by ablation of Yap in tubular cells. Inhibition of KLF5 prevented tubular cell overproliferation, tubular injury, and renal inflammation in Mst1/2 dKO kidneys. Therefore, our results demonstrate that tubular YAP is a key player in kidney injury. YAP and KLF5 form a transcriptional cascade, where tubular YAP activation induced by kidney injury promotes KLF5 transcription. Activation of this cascade induces tubular cell overproliferation, tubular injury, and renal inflammation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Túbulos Renais , Fatores de Transcrição Kruppel-Like , Camundongos Knockout , Proteínas de Sinalização YAP , Animais , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Proteínas de Sinalização YAP/metabolismo , Proteínas de Sinalização YAP/genética , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Túbulos Renais/citologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Serina-Treonina Quinase 3 , Transdução de Sinais , Proliferação de Células , Regulação da Expressão Gênica , Modelos Animais de Doenças , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia , Cisplatino/farmacologiaRESUMO
Through Smad3-dependent signalings, transforming growth factor-ß (TGF-ß) suppresses the development, maturation, cytokine productions and cytolytic functions of NK cells in cancer. Silencing Smad3 remarkably restores the cytotoxicity of NK-92 against cancer in TGF-ß-rich microenvironment, but its effects on the immunoregulatory functions of NK cells remain obscure. In this study, we identified Smad3 functioned as a transcriptional repressor for CSF2 (GM-CSF) in NK cells. Therefore, disrupting Smad3 largely mitigated TGF-ß-mediated suppression on GM-CSF production by NK cells. Furthermore, silencing GM-CSF in Smad3 knockout NK cells substantially impaired their anti-lung carcinoma effects. In-depth study demonstrated that NK-derived GM-CSF strengthened T cell immune responses by stimulating dendritic cell differentiation and M1 macrophage polarization. Meanwhile, NK-derived GM-CSF promoted the survival of neutrophils, which in turn facilitated the terminal maturation of NK cells, and subsequently boosted NK-cell mediated cytotoxicity against lung carcinoma. Thus, Smad3-silenced NK-92 (NK-92-S3KD) may serve as a promising immunoadjuvant therapy with clinical translational value given its robust cytotoxicity against malignant cells and immunostimulatory functions to reinforce the therapeutic effects of other immunotherapies.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos , Células Matadoras Naturais , Neoplasias Pulmonares , Proteína Smad3 , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Proteína Smad3/metabolismo , Proteína Smad3/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Diferenciação Celular , Macrófagos/metabolismo , Macrófagos/imunologia , Transdução de SinaisRESUMO
AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Insuficiência Renal Crônica , Humanos , Nefropatias Diabéticas/metabolismo , Doenças Cardiovasculares/complicações , Estudos Prospectivos , Hong Kong/epidemiologia , Albuminúria , Bancos de Espécimes Biológicos , Taxa de Filtração Glomerular , Biomarcadores , AlbuminasRESUMO
Increasing evidence shows that SARS-CoV-2 can infect kidneys and cause acute kidney injury (AKI) in critically ill COVID-19 patients. However, mechanisms through which COVID-19 induces AKI are largely unknown, and treatment remains ineffective. Here, we report that kidney-specific overexpressing SARS-CoV-2 N gene can cause AKI, including tubular necrosis and elevated levels of serum creatinine and BUN in 8-week-old diabetic db/db mice, which become worse in those with older age (16 weeks) and underlying diabetic kidney disease (DKD). Treatment with quercetin, a purified product from traditional Chinese medicine (TCM) that shows effective treatment of COVID-19 patients, can significantly inhibit SARS-CoV-2 N protein-induced AKI in diabetic mice with or without underlying DKD. Mechanistically, quercetin can block the binding of SARS-CoV-2 N protein to Smad3, thereby inhibiting Smad3 signaling and Smad3-mediated cell death via the p16-dependent G1 cell-cycle arrest mechanism in vivo and in vitro. In conclusion, SARS-CoV-2 N protein is pathogenic and can cause severe AKI in diabetic mice, particularly in those with older age and pre-existing DKD, via the Smad3-dependent G1 cell-cycle arrest mechanism. Importantly, we identify that quercetin may be an effective TCM compound capable of inhibiting COVID-19 AKI by blocking SARS-CoV-2 N-Smad3-mediated cell death pathway.
Assuntos
Injúria Renal Aguda , COVID-19 , Diabetes Mellitus Experimental , Camundongos , Animais , SARS-CoV-2 , COVID-19/complicações , Quercetina/farmacologia , Diabetes Mellitus Experimental/complicações , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Camundongos Endogâmicos , Pontos de Checagem do Ciclo CelularRESUMO
Gastrin-releasing peptide (GRP) binds to its receptor (GRP receptor [GRPR]) to regulate multiple biological processes, but the function of GRP/GRPR axis in acute kidney injury (AKI) remains unknown. In the present study, GRPR is highly expressed by tubular epithelial cells (TECs) in patients or mice with AKI, while histone deacetylase 8 may lead to the transcriptional activation of GRPR. Functionally, we uncovered that GRPR was pathogenic in AKI, as genetic deletion of GRPR was able to protect mice from cisplatin- and ischemia-induced AKI. This was further confirmed by specifically deleting the GRPR gene from TECs in GRPRFlox/Flox//KspCre mice. Mechanistically, we uncovered that GRPR was able to interact with Toll-like receptor 4 to activate STAT1 that bound the promoter of MLKL and CCL2 to induce TEC necroptosis, necroinflammation, and macrophages recruitment. This was further confirmed by overexpressing STAT1 to restore renal injury in GRPRFlox/Flox/KspCre mice. Concurrently, STAT1 induced GRP synthesis to enforce the GRP/GRPR/STAT1 positive feedback loop. Importantly, targeting GRPR by lentivirus-packaged small hairpin RNA or by treatment with a novel GRPR antagonist RH-1402 was able to inhibit cisplatin-induced AKI. In conclusion, GRPR is pathogenic in AKI and mediates AKI via the STAT1-dependent mechanism. Thus, targeting GRPR may be a novel therapeutic strategy for AKI.
Assuntos
Injúria Renal Aguda , Cisplatino , Animais , Camundongos , Cisplatino/efeitos adversos , Necroptose , Injúria Renal Aguda/metabolismo , Rim/metabolismo , Inflamação/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Follistatin (FS)-like 1 (FSTL1) is a member of the FS-SPARC (secreted protein, acidic and rich in cysteine) family of secreted and extracellular matrix proteins. The functions of FSTL1 have been studied in heart and lung injury as well as in wound healing; however, the role of FSTL1 in the kidney is largely unknown. Here, we show using single-cell RNA-Seq that Fstl1 was enriched in stromal cells in obstructed mouse kidneys. In addition, immunofluorescence demonstrated that FSTL1 expression was induced in fibroblasts during kidney fibrogenesis in mice and human patients. We demonstrate that FSTL1 overexpression increased renal fibrosis and activated the Wnt/ß-catenin signaling pathway, known to promote kidney fibrosis, but not the transforming growth factor ß (TGF-ß), Notch, Hedgehog, or Yes-associated protein (YAP) signaling pathways in obstructed mouse kidneys, whereas inhibition of FSTL1 lowered Wnt/ß-catenin signaling. Importantly, we show that FSTL1 interacted with Wnt ligands and the Frizzled (FZD) receptors but not the coreceptor lipoprotein receptor-related protein 6 (LRP6). Specifically, we found FSTL1 interacted with Wnt3a through its extracellular calcium-binding (EC) domain and von Willebrand factor type C-like (VWC) domain, and with FZD4 through its EC domain. Furthermore, we show that FSTL1 increased the association of Wnt3a with FZD4 and promoted Wnt/ß-catenin signaling and fibrogenesis. The EC domain interacting with both Wnt3a and FZD4 also enhanced Wnt3a signaling. Therefore, we conclude that FSTL1 is a novel extracellular enhancer of the Wnt/ß-catenin pathway.
Assuntos
Proteínas Relacionadas à Folistatina , Receptores Frizzled , Rim , Via de Sinalização Wnt , Animais , Proteínas Relacionadas à Folistatina/genética , Proteínas Relacionadas à Folistatina/metabolismo , Receptores Frizzled/metabolismo , Humanos , Rim/metabolismo , Rim/fisiopatologia , Ligantes , Camundongos , Proteína Wnt3ARESUMO
Final urine volume and concentration are defined by water reabsorption through the water channel proteins aquaporin (AQP)-2, -3 and -4 in the collecting duct. However, the transcriptional regulation of these AQPs is not well understood. The Hippo/Yes-associated protein 1 (YAP) pathway plays an important role in organ size control and tissue homeostasis. When the Hippo pathway including the Mst1/Mst2 kinases is inhibited, YAP is activated and functions as a transcription co-activator. Our previous work revealed a pathological role of tubular YAP activation in chronic kidney disease, but the physiological role of YAP in the kidney remains to be established. Here, we found that tubule-specific Yap knockout mice showed increased urine output and decreased urinary osmolality. Decreases in Aqp2, -3 and -4 mRNA and protein abundance in the kidney were evident in Yap knockout mice. Analysis of Mst1/Mst2 double knockout and Mst1/Mst2/Yap triple knockout mice showed that expression of Aqp2 and Aqp4 but not Aqp3 was dependent on YAP. Furthermore, YAP was recruited to the promoters of the Aqp2 and Aqp4 genes and stimulated their transcription. Interestingly, YAP was found to interact with transcription factors GATA2, GATA3 and NFATc1. These three factors promoted Aqp2 transcription in a YAP dependent manner in collecting duct cells. These three factors also promoted Aqp4 transcription whereas only GATA2 and GATA3 enhanced Aqp3 transcription. Thus, our results suggest that YAP promotes Aqp2 and Aqp4 transcription, interacts with GATA2, GATA3 and NFATc1 to control Aqp2 expression, while Aqp-2, -3 and -4 exploit overlapping mechanisms for their baseline transcriptional regulation.
Assuntos
Aquaporina 2 , Túbulos Renais Coletores , Camundongos , Animais , Aquaporina 2/metabolismo , Proteínas de Sinalização YAP , Rim/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fatores de Transcrição/metabolismo , Camundongos Knockout , Água/metabolismo , Homeostase , Túbulos Renais Coletores/metabolismoRESUMO
Clopidogrel, a P2Y12 inhibitor, is a novel anti-fibrosis agent for chronic kidney disease (CKD), but its mechanisms remain unclear, which we investigated by silencing P2Y12 or treating unilateral ureteral obstruction (UUO) in LysM-Cre/Rosa Tomato mice with clopidogrel in vivo and in vitro. We found that P2Y12 was significantly increased and correlated with progressive renal fibrosis in CKD patients and UUO mice. Phenotypically, up to 82% of P2Y12-expressing cells within the fibrosing kidney were of macrophage origin, identified by co-expressing CD68/F4/80 antigens or a macrophage-lineage-tracing marker Tomato. Unexpectedly, more than 90% of P2Y12-expressing macrophages were undergoing macrophage-to-myofibroblast transition (MMT) by co-expressing alpha smooth muscle actin (α-SMA), which was also confirmed by single-cell RNA sequencing. Functionally, clopidogrel improved the decline rate of the estimated glomerular filtration rate (eGFR) in patients with CKD and significantly inhibited renal fibrosis in UUO mice. Mechanistically, P2Y12 expression was induced by transforming growth factor ß1 (TGF-ß1) and promoted MMT via the Smad3-dependent mechanism. Thus, silencing or pharmacological inhibition of P2Y12 was capable of inhibiting TGF-ß/Smad3-mediated MMT and progressive renal fibrosis in vivo and in vitro. In conclusion, P2Y12 is highly expressed by macrophages in fibrosing kidneys and mediates renal fibrosis by promoting MMT via TGF-ß/Smad3 signaling. Thus, P2Y12 inhibitor maybe a novel and effective anti-fibrosis agent for CKD.
Assuntos
Nefropatias , Insuficiência Renal Crônica , Obstrução Ureteral , Animais , Clopidogrel/metabolismo , Clopidogrel/farmacologia , Clopidogrel/uso terapêutico , Fibrose , Rim , Nefropatias/etiologia , Nefropatias/genética , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/genéticaRESUMO
Plasma levels of neuropeptide Y (NPY) are elevated in patients with acute myocardial infarction (AMI), but its role in AMI remains unclear, which was examined here in NPY wild-type/knockout (WT/KO) mice treated with/without exogenous NPY and its Y1 receptor antagonist (Y1Ra) BIBP 3226. We found that AMI mice lacking NPY developed more severe AMI than WT mice with worse cardiac dysfunction, progressive cardiac inflammation and fibrosis, and excessive apoptosis but impairing angiogenesis. All of these changes were reversed when the NPY KO mice were treated with exogenous NPY in a dose-dependent manner. Interestingly, treatment with NPY also dose dependently attenuated AMI in WT mice, which was blocked by BIBP 3226. Phenotypically, cardiac NPY was de novo expressed by infiltrating macrophages during the repairing or fibrosing process in heart-failure patients and AMI mice. Mechanistically, NPY was induced by transforming growth factor (TGF)-ß1 in bone marrow-derived macrophages and signaled through its Y1R to exert its pathophysiological activities by inhibiting p38/nuclear factor κB (NF-κB)-mediated M1 macrophage activation while promoting the reparative M2 phenotype in vivo and in vitro. In conclusion, NPY can attenuate AMI in mice. Inhibition of cardiac inflammation and fibrosis while enhancing angiogenesis but reducing apoptosis may be the underlying mechanisms through which NPY attenuates cardiac remodeling and deterioration of function following AMI.
Assuntos
Infarto do Miocárdio , Neuropeptídeo Y , Animais , Humanos , Camundongos , Camundongos Knockout , Infarto do Miocárdio/sangue , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Neuropeptídeo Y/sangue , Neuropeptídeo Y/genética , Remodelação VentricularRESUMO
Unresolved inflammation can lead to tissue fibrosis and impaired organ function. Macrophage-myofibroblast transition (MMT) is one newly identified mechanism by which ongoing chronic inflammation causes progressive fibrosis in different forms of kidney disease. However, the mechanisms underlying MMT are still largely unknown. Here, we discovered a brain-specific homeobox/POU domain protein Pou4f1 (Brn3a) as a specific regulator of MMT. Interestingly, we found that Pou4f1 is highly expressed by macrophages undergoing MMT in sites of fibrosis in human and experimental kidney disease, identified by coexpression of the myofibroblast marker, α-SMA. Unexpectedly, Pou4f1 expression peaked in the early stage in renal fibrogenesis in vivo and during MMT of bone marrow-derived macrophages (BMDMs) in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assay identified that Pou4f1 is a Smad3 target and the key downstream regulator of MMT, while microarray analysis defined a Pou4f1-dependent fibrogenic gene network for promoting TGF-ß1/Smad3-driven MMT in BMDMs at the transcriptional level. More importantly, using two mouse models of progressive renal interstitial fibrosis featuring the MMT process, we demonstrated that adoptive transfer of TGF-ß1-stimulated BMDMs restored both MMT and renal fibrosis in macrophage-depleted mice, which was prevented by silencing Pou4f1 in transferred BMDMs. These findings establish a role for Pou4f1 in MMT and renal fibrosis and suggest that Pou4f1 may be a therapeutic target for chronic kidney disease with progressive renal fibrosis.
Assuntos
Proteína Smad3/metabolismo , Fator de Transcrição Brn-3A/genética , Fator de Crescimento Transformador beta1/metabolismo , Animais , Feminino , Fibrose/fisiopatologia , Redes Reguladoras de Genes , Humanos , Inflamação/patologia , Rim/patologia , Nefropatias/genética , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Transdução de Sinais/genética , Fator de Transcrição Brn-3A/metabolismo , Fator de Transcrição Brn-3A/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Sistema Urinário/metabolismoRESUMO
Transforming growth factor-ß (TGF-ß)/Smad3 signaling has been shown to play important roles in fibrotic and inflammatory diseases. However, the role of Smad3 in dyslipidemia and non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes remains unclear, and whether targeting Smad3 has a therapeutic effect on these metabolic abnormalities remains unexplored. These topics were investigated in this study in Smad3 knockout (KO)-db/db mice and by treating db/db mice with a Smad3-specific inhibitor SIS3. Compared to Smad3 wild-type (WT)-db/db mice, Smad3 KO-db/db mice were protected against dyslipidemia and NAFLD. Similarly, treatment of db/db mice with SIS3 at week 4 before the onset of type 2 diabetes until week 12 was capable of lowering blood glucose levels and improving diabetic dyslipidemia and NAFLD. In addition, using RNA-sequencing, the potential Smad3-target genes related to lipid metabolism was identified in the liver tissues of Smad3 KO/WT mice, and the regulatory mechanisms were investigated. Mechanistically, we uncovered that Smad3 targeted peroxisome proliferator-activated receptor delta (PPARδ) to induce dyslipidemia and NAFLD in db/db mice, which was improved by genetically deleting and pharmacologically inhibiting Smad3.
Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , PPAR delta , Proteína Smad3 , Animais , Camundongos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , PPAR delta/metabolismo , Proteína Smad3/metabolismoRESUMO
Diabetic nephropathy (DN) is a common complication of diabetes and a leading cause of end-stage renal disease. Transforming growth factor-ß1 (TGF-ß1)/SMAD signaling activation plays an important role in the onset and progression of DN. Reported findings suggest that the activation of TGF-ß1 (including the latent form, the active form, and the receptors) and its downstream signaling proteins (SMAD3, SMAD7, etc.) plays a critical role in DN. In addition, TGF-ß1/SMAD signaling may mediate the pathogenesis and progression of DN via various microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Emerging evidence shows that TGF-ß1, SMAD3, and SMAD7 are the main signaling proteins that contribute to the development of DN, and that they can be potential targets for the treatment of DN. However, recent clinical trials have shown that the anti-TGF-ß1 monoclonal antibody treatment fails to effectively alleviate DN, which suggests that upstream inhibition of TGF-ß1/SMAD signaling does not alleviate clinical symptoms and that this may be related to the fact that TGF-ß1/SMAD has multiple biological effects. Targeted inhibition of the downstream TGF-ß1 signaling (e.g., SMAD3 and SMAD7) may be an effective approach to attenuate DN. This article discussed the current understanding of the molecular mechanisms and potential targets for the treatment and prevention of DN by focusing on TGF-ß1/SMAD signaling.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Proteínas Smad , Fator de Crescimento Transformador beta1 , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , MicroRNAs , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Smad/metabolismoRESUMO
RATIONALE & OBJECTIVE: Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing DKD phenotype. We compared the risks of adverse outcomes among patients with this phenotype compared with other DKD phenotypes. STUDY DESIGN: Multicenter prospective cohort study. SETTINGS & PARTICIPANTS: 19,025 Chinese adults with type 2 diabetes enrolled in the Hong Kong Diabetes Biobank. EXPOSURES: DKD phenotypes defined by baseline estimated glomerular filtration rate (eGFR) and albuminuria: no DKD (no decreased eGFR or albuminuria), albuminuria without decreased eGFR, decreased eGFR without albuminuria, and albuminuria with decreased eGFR. OUTCOMES: All-cause mortality, cardiovascular disease (CVD) events, hospitalization for heart failure (HF), and chronic kidney disease (CKD) progression (incident kidney failure or sustained eGFR reduction ≥40%). ANALYTICAL APPROACH: Multivariable Cox proportional or cause-specific hazards models to estimate the relative risks of death, CVD, hospitalization for HF, and CKD progression. Multiple imputation was used for missing covariates. RESULTS: Mean participant age was 61.1 years, 58.3% were male, and mean diabetes duration was 11.1 years. During 54,260 person-years of follow-up, 438 deaths, 1,076 CVD events, 298 hospitalizations for HF, and 1,161 episodes of CKD progression occurred. Compared with the no-DKD subgroup, the subgroup with decreased eGFR without albuminuria had higher risks of all-cause mortality (hazard ratio [HR], 1.59 [95% CI, 1.04-2.44]), hospitalization for HF (HR, 3.08 [95% CI, 1.82-5.21]), and CKD progression (HR, 2.37 [95% CI, 1.63-3.43]), but the risk of CVD was not significantly greater (HR, 1.14 [95% CI, 0.88-1.48]). The risks of death, CVD, hospitalization for HF, and CKD progression were higher in the setting of albuminuria with or without decreased eGFR. A sensitivity analysis that excluded participants with baseline eGFR <30 mL/min/1.73 m2 yielded similar findings. LIMITATIONS: Potential misclassification because of drug use. CONCLUSIONS: Nonalbuminuric DKD was associated with higher risks of hospitalization for HF and of CKD progression than no DKD, regardless of baseline eGFR.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Insuficiência Cardíaca , Insuficiência Renal Crônica , Albuminúria/epidemiologia , Bancos de Espécimes Biológicos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/complicações , Feminino , Taxa de Filtração Glomerular , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/epidemiologia , Hong Kong/epidemiologia , Humanos , Rim , Masculino , Estudos Prospectivos , Insuficiência Renal Crônica/complicaçõesRESUMO
OBJECTIVE: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. RESEARCH DESIGN AND METHODS: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. RESULTS: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model. CONCLUSION: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Adulto , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Bancos de Espécimes Biológicos , Hong Kong/epidemiologia , Fatores de Risco , Lipoproteínas HDL , HDL-ColesterolRESUMO
Diabetic nephropathy (DN) is a major cause of end-stage renal disease, but treatment remains ineffective. C-reactive protein (CRP) is pathogenic in DN, which significantly correlated with dipeptidyl peptidase-4 (DPP4) expression in diabetic patients with unknown reason. Here, using our unique CRPtg-db/db mice, we observed human CRP markedly induced renal DPP4 associated with enhanced kidney injury compared with db/db mice. Interestingly, linagliptin, a US Food and Drug Administration (FDA)-approved specific DPP4 inhibitor, effectively blocked this CRP-driven DN in the CRPtg-db/db mice. Mechanistically, CRP evoked DPP4 in cultured renal tubular epithelial cells, where CD32b/nuclear factor κB (NF-κB) signaling markedly enriched p65 binding on the DPP4 promoter region to increase its transcription. Unexpectedly, we further discovered that CRP triggers dimerization of DPP4 with CD32b at protein level, forming a novel DPP4/CD32b/NF-κB signaling circuit for promoting CRP-mediated DN. More importantly, linagliptin effectively blocked the circuit, thereby inhibiting the CRP/CD32b/NF-κB-driven renal inflammation and fibrosis. Thus, DPP4 may represent a precise druggable target for CRP-driven DN.
Assuntos
Proteína C-Reativa/metabolismo , Nefropatias Diabéticas/metabolismo , Dipeptidil Peptidase 4/metabolismo , NF-kappa B/metabolismo , Receptores de IgG/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Diabetes Mellitus Experimental , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Regulação da Expressão Gênica , CamundongosRESUMO
Increasing evidence shows that long non-coding RNAs (lncRNAs) play an important role in a variety of disorders including kidney diseases. It is well recognized that inflammation is the initial step of kidney injury and is largely mediated by nuclear factor Kappa B (NF-κB) signaling. We had previously identified lncRNA-Arid2-IR is an inflammatory lncRNA associated with NF-κB-mediated renal injury. In this study, we examined the regulatory mechanism through which Arid2-IR activates NF-κB signaling. We found that Arid2-IR was differentially expressed in response to various kidney injuries and was induced by transforming growth factor beta 1(TGF-ß1). Using RNA sequencing and luciferase assays, we found that Arid2-IR regulated the activity of NF-κB signal via NLRC5-dependent mechanism. Arid2-IR masked the promoter motifs of NLRC5 to inhibit its transcription. In addition, during inflammatory response, Filamin A (Flna) was increased and functioned to trap Arid2-IR in cytoplasm, thereby preventing its nuclear translocation and inhibition of NLRC5 transcription. Thus, lncRNA Arid2-IR mediates NF-κB-driven renal inflammation via a NLRC5-dependent mechanism and targeting Arid2-IR may be a novel therapeutic strategy for inflammatory diseases in general.
Assuntos
Inflamação/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Rim/metabolismo , NF-kappa B/metabolismo , RNA Longo não Codificante/genética , Transcrição Gênica , Animais , Células Cultivadas , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
Renal inflammation is an initial pathological process during progressive renal injury regardless of the initial cause. Macrophage migration inhibitory factor (MIF) is a truly proinflammatory stress mediator that is highly expressed in a variety of both inflammatory cells and intrinsic kidney cells. MIF is released from the diseased kidney immediately upon stimulation to trigger renal inflammation by activating macrophages and T cells, and promoting the production of proinflammatory cytokines, chemokines, and stress molecules via signaling pathways involving the CD74/CD44 and chemokine receptors CXCR2, CXCR4, and CXCR7 signaling. In addition, MIF can function as a stress molecule to counter-regulate the immunosuppressive effect of glucocorticoid in renal inflammation. Given the critical position of MIF in the upstream inflammatory cascade, this review focuses on the regulatory role and molecular mechanisms of MIF in kidney diseases. The therapeutic potential of targeting MIF signaling to treat kidney diseases is also discussed.
Assuntos
Fatores Inibidores da Migração de Macrófagos , Nefrite , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Inflamação , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Nefrite/metabolismo , Receptores de Interleucina-8B , Transdução de Sinais , Estresse Fisiológico/fisiologiaRESUMO
Rheumatoid arthritis (RA) is a common disease worldwide and is treated commonly with methotrexate (MTX). CS12192 is a novel JAK3 inhibitor discovered by Chipscreen Biosciences for the treatment of autoimmune diseases. In the present study, we examined the therapeutic effect of CS12192 against RA and explored if the combinational therapy of CS12192 and MTX produced a synergistic effect against RA in rat collagen-induced arthritis (CIA). Arthritis was induced in male Sprague-Dawley rats by two intradermal injections of bovine type II collagen (CII) and treated with MTX, CS12192, or the combination of CS12192 and MTX daily for two weeks. Effects of different treatments on arthritis score, X-ray score, pathology, and expression of inflammatory cytokines and biomarkers were examined. We found that treatment with either CS12192 or MTX produced a comparable therapeutic effect on CIA including: (1) significantly lowering the arthritis score, X-ray score, serum levels of rheumatic factor (RF), C-reactive protein (CRP), and anti-nuclear antibodies (ANA); (2) largely alleviating histopathological damage, reducing infiltration of Th17 cells while promoting Treg cells; (3) inhibiting the expression of inflammatory cytokines and chemokines such as IL-1ß, TNF-α, IL-6, CCL2, and CXCL1. All these inhibitory effects were further improved by the combinational therapy with MTX and CS12192. Of importance, the combinational treatment also resulted in a marked switching of the Th17 to Treg and the M1 to M2 immune responses in synovial tissues of CIA. Thus, when compared to the monotherapy, the combination treatment with CS12192 and MTX produces a better therapeutic effect against CIA with a greater suppressive effect on T cells and macrophage-mediated joint inflammation.
Assuntos
Artrite Experimental , Artrite Reumatoide , Inibidores de Janus Quinases , Ratos , Masculino , Bovinos , Animais , Metotrexato/uso terapêutico , Ratos Sprague-Dawley , Artrite Experimental/patologia , Citocinas/metabolismo , Inibidores de Janus Quinases/efeitos adversosRESUMO
Diabetic cardiomyopathy (DCM) is a common diabetic complication characterized by diastolic relaxation abnormalities, myocardial fibrosis and chronic heart failure. Although TGF-ß/Smad3 signalling has been shown to play a critical role in chronic heart disease, the role and mechanisms of Smad3 in DCM remain unclear. We reported here the potential role of Smad3 in the development of DCM by genetically deleting the Smad3 gene from db/db mice. At the age of 32 weeks, Smad3WT-db/db mice developed moderate to severe DCM as demonstrated by a marked increase in the left ventricular (LV) mass, a significant fall in the LV ejection fraction (EF) and LV fractional shortening (FS), and progressive myocardial fibrosis and inflammation. In contrast, db/db mice lacking Smad3 (Smad3KO-db/db) were protected against the development of DCM with normal cardiac function and undetectable myocardial inflammation and fibrosis. Interestingly, db/db mice with deleting one copy of Smad3 (Smad3 ± db/db) did not show any cardioprotective effects. Mechanistically, we found that deletion of Smad3 from db/db mice largely protected cardiac Smad7 from Smurf2-mediated ubiquitin proteasome degradation, thereby inducing IBα to suppress NF-kB-driven cardiac inflammation. In addition, deletion of Smad3 also altered Smad3-dependent miRNAs by up-regulating cardiac miR-29b while suppressing miR-21 to exhibit the cardioprotective effect on Smad3KO-db/db mice. In conclusion, results from this study reveal that Smad3 is a key mediator in the pathogenesis of DCM. Targeting Smad3 may be a novel therapy for DCM.