RESUMO
Chronic kidney disease (CKD) is an emerging cause for morbidity and mortality worldwide. Acute kidney injury (AKI) can transition to CKD and finally to end-stage renal disease (ESRD). Targeted treatment is still unavailable. NF-κB signaling is associated with CKD and activated by B cell activating factor (BAFF) via BAFF-R binding. In turn, renal tubular epithelial cells (TECs) are critical for the progression of fibrosis and producing BAFF. Therefore, the direct involvement of the BAFF/BAFF-R system to the pathogenesis of CKD is conceivable. We performed non-accelerated nephrotoxic serum nephritis (NTN) as the CKD model in BAFF KO (B6.129S2-Tnfsf13btm1Msc/J), BAFF-R KO (B6(Cg)-Tnfrsf13ctm1Mass/J) and wildtype (C57BL/6J) mice to analyze the BAFF/BAFF-R system in anti-glomerular basement membrane (GBM) disease using high throughput RNA sequencing. We found that BAFF signaling is directly involved in the upregulation of collagen III as BAFF ko mice showed a reduced expression. However, these effects were not mediated via BAFF-R. We identified several upregulated genes that could explain the effects of BAFF in chronic kidney injury such as Txnip, Gpx3, Igfbp7, Ccn2, Kap, Umod and Ren1. Thus, we conclude that targeted treatment with anti-BAFF drugs such as belimumab may reduce chronic kidney damage. Furthermore, upregulated genes may be useful prognostic CKD biomarkers.
Assuntos
Fator Ativador de Células B , Receptor do Fator Ativador de Células B , Nefrite , Transcriptoma , Animais , Masculino , Camundongos , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrite/metabolismo , Nefrite/genética , Nefrite/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Transdução de SinaisRESUMO
INTRODUCTION: Hypertensive nephrosclerosis (HN) ranks as one of the most frequent causes of chronic kidney disease (CKD), but its very existence has repeatedly been called into question, especially in young adults. Its diagnostic framework is established chiefly on non-specific clinical criteria, and its defining histopathological set of features is in fact shared by numerous other conditions. Genetic testing based on exome sequencing (ES) has emerged as a comprehensive tool to detect Mendelian diseases in timely fashion in nephrology, with a significant number of re-established diagnoses. The aim of this study was to investigate the diagnostic yield of ES in patients with a clinical diagnosis of hypertensive nephropathy. METHOD: Since September 2018, ES has been readily available as part of the routine diagnostic work-up in our institution. The indication of ES includes hypertensive nephropathy of early onset (i.e., <45 years old). We retrospectively collected the ES data performed in the context of hypertensive nephropathy in our institution between September 2018 and February 2021. RESULTS: A total of 128 patients were sequenced in the context of hypertensive nephropathy with early onset. The chief indications of ES were an early onset of CKD (47%), family history of kidney disease (8%), or both (18%). We detected diagnostic variants in 19 of the 128 patients (15%), encompassing a total of 13 different monogenic disorders. The diagnostic yield of ES was lower in patients of African ancestry (diagnostic yield of 7 vs. 30% in non-African ancestry patients, p < 0.001). CONCLUSIONS: The high diagnostic yield of ES (15%) in a population of patients thought to have HN casts further doubts on the validity of the existing diagnosis criteria, including histological criteria, supposed to characterize the condition. This was especially true in patients with no African ancestry, where ES positivity reached 30%.
Assuntos
Sequenciamento do Exoma , Hipertensão Renal , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Hipertensão Renal/genética , Hipertensão Renal/diagnóstico , Idade de Início , Nefrite/genética , Nefrite/diagnóstico , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/diagnóstico , Nefroesclerose/genética , Nefroesclerose/diagnósticoRESUMO
Chronic kidney disease (CKD) is characterized by kidney inflammation and fibrosis. However, the precise mechanisms leading to kidney inflammation and fibrosis are poorly understood. Since histone deacetylase is involved in inflammation and fibrosis in other tissues, we examined the role of histone deacetylase 3 (HDAC3) in the regulation of inflammation and kidney fibrosis. HDAC3 is induced in the kidneys of animal models of CKD but mice with conditional HDAC3 deletion exhibit significantly reduced fibrosis in the kidneys compared with control mice. The expression of proinflammatory and profibrotic genes was significantly increased in the fibrotic kidneys of control mice, which was impaired in mice with HDAC3 deletion. Genetic deletion or pharmacological inhibition of HDAC3 reduced the expression of proinflammatory genes in cultured monocytes/macrophages. Mechanistically, HDAC3 deacetylates Lys122 of NF-κB p65 subunit turning on transcription. RGFP966, a selective HDAC3 inhibitor, reduced fibrosis in cells and in animal models by blocking NF-κB p65 binding to κB-containing DNA sequences. Thus, our study identified HDAC3 as a critical regulator of inflammation and fibrosis of the kidney through deacetylation of NF-κB unlocking its transcriptional activity. Hence, targeting HDAC3 could serve as a novel therapeutic strategy for CKD.
Assuntos
Histona Desacetilases , Nefrite , Insuficiência Renal Crônica , Animais , Camundongos , Fibrose , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Inflamação/genética , Inflamação/patologia , Rim/patologia , Nefrite/genética , Nefrite/patologia , NF-kappa B/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologiaRESUMO
This study investigated the impacts of CCR5 promoter region polymorphisms on the development of systemic lupus erythematosus (SLE) by comparing CCR5 genotypes and haplotypes from SLE patients with ethnically matched controls. A total of 382 SLE patients (289 European-derived and 93 African-derived) and 375 controls (243 European-derived and 132 African-derived) were genotyped for the CCR2-64I G > A (rs1799864), CCR5-59353 C > T (rs1799988), CCR5-59356 C > T (rs41469351), CCR5-59402 A > G (rs1800023) and CCR5-59653 C > T (rs1800024) polymorphisms through polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Previous data from CCR5Δ32 analysis was included in the study to infer the CCR5 haplotypes and as a possible confounding factor in the binary logistic regression. European-derived patients showed a higher frequency of CCR5 wild-type genotype (conversely, a reduced frequency of Δ32 allele) and a reduced frequency of the HHG*2 haplotype compared to controls; both factors significantly affecting disease risk [p = .003 (OR 3.5, 95%CI 1.6-7.5) and 2.0% vs. 7.2% (residual p = 2.9E - 5), respectively]. Additionally, the HHA/HHB, HHC and HHG*2 haplotype frequencies differed between African-derived patients and controls [10% vs. 20.5% (residual p = .003), 29.4% vs. 17.4% (residual p = .003) and 3.9% vs. 0.8% (residual p = .023), respectively]. Considering the clinical manifestations of the disease, the CCR5Δ32 presence was confirmed as a susceptibility factor to class IV nephritis in the African-derived group and when all patients were grouped for comparison [pcorrected = .012 (OR 3.0; 95%CI 3.0-333.3) and pcorrected = .0006 (OR 6.8; 95%CI 1.9-24.8), respectively]. In conclusion, this study indicates that CCR5 promoter polymorphisms are important disease modifiers in SLE. Present data reinforces the CCR5Δ32 polymorphism as a protective factor for the development of the disease in European-derived patients and as a susceptibility factor for class IV nephritis in African-derived patients. Furthermore, we also described a reduced frequency of HHA/HHB and an increased frequency of HHC and HHG*2 haplotypes in African-derived patients, which could modify the CCR5 protein expression in specific cell subsets.
Assuntos
Lúpus Eritematoso Sistêmico , Nefrite , Humanos , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Genótipo , Nefrite/genética , Receptores CCR5/genética , Regiões Promotoras Genéticas/genética , Frequência do Gene , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Henoch-Schönlein purpura nephritis (HSPN) is a common vasculitis that mostly affects children, and previous studies have indicated that genetic factors may influence disease susceptibility. The aim of this study was to evaluate a possible association of three interleukin-2 (IL-2) gene polymorphisms (rs3136534, rs2069776, and rs2069762) with HSPN in the Chinese population. A total of 81 patients with HSPN and 200 healthy children were enrolled. The distribution of genotypes, allelic frequencies, and haplotype frequencies among the three IL-2 polymorphisms were analyzed using the Sequenom MassARRAY system by means of matrix-assisted laser desorption ionization-time of flight mass spectrometry method. Compared to the healthy controls, genotyping analysis demonstrated rs3136534 was associated with a decreased HSPN risk in the dominant inheritance model (G/T+T/T vs. G/G; OR, 0.54; 95% CI, 0.31-0.93). However, the frequency of the T allele and haplotypes of rs3136534 showed no statistical significance. For the frequency of genotype, allele, and haplotype of the rs2069776 and rs20697622 polymorphisms, no significant differences were observed between HSPN patients and controls. Our results suggest that the rs3136534 polymorphism of the IL-2 gene is associated with susceptibility to HSPN in Chinese children.
Assuntos
Vasculite por IgA , Nefrite , Criança , Humanos , Predisposição Genética para Doença , Vasculite por IgA/genética , Vasculite por IgA/complicações , Interleucina-2/genética , Nefrite/genética , Nefrite/complicações , Polimorfismo de Nucleotídeo ÚnicoRESUMO
It has been demonstrated in many studies that angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism is related to Henoch-Schonlein purpura nephritis (HSPN) risk in children. However, this conclusion remains controversial. In this study, we systemically retrieved relevant studies in electronic databases such as PUBMED, CNKI, and EMBASE followed by calculation of odds ratios (OR) with 95% confidence intervals (CI). In addition, meta-package in STATA version 12.0 was used. Angiotensin-converting enzyme I/D polymorphism was related to HSPN susceptibility in children (D vs. I: OR 1.47, 95% CI: 1.13-1.93; DD vs. II: OR 2.29, 95% CI: 1.29-4.07; DI vs. II: OR 1.10, 95% CI: 0.82-1.48; dominant model: OR 1.44, 95% CI: 1.09-1.89; recessive model: OR 2.26, 95% CI: 1.67-3.06). In addition, subgroup analysis stratified according to ethnicity indicated a significant relationship between this polymorphism and HSPN susceptibility among Asians and Caucasians. The data extracted from HaploReg indicated that ACE I/D polymorphism was not in linkage disequilibrium with other variants in the ACE gene. The research shows that ACE I/D polymorphism is related to HSPN susceptibility in children.
Assuntos
Vasculite por IgA , Nefrite , Humanos , Criança , Vasculite por IgA/genética , Razão de Chances , Polimorfismo Genético , Angiotensinas , Nefrite/genéticaRESUMO
Background The renal mechanisms involved in the maintenance of human hypertension and resistance to treatment are not well understood. Animal studies suggest that chronic renal inflammation contributes to hypertension. We studied cells shed in first-morning urine samples from individuals who were hypertensive who exhibited difficult-to-control blood pressure (BP). We performed bulk RNA sequencing of these shed cells to develop transcriptome-wide associations with BP. We also analyzed nephron-specific genes and used an unbiased bioinformatic approach to find signaling pathways activated in difficult-to-control hypertension. Methods and Results Participants who completed the SPRINT (Systolic Blood Pressure Intervention Trial) at a single trial site were recruited, and cells shed in first-morning urine samples collected. A total of 47 participants were divided into 2 groups based on hypertension control. The BP-difficult group (n=29) had systolic BP>140 mm Hg, >120 mm Hg after intensive treatment for hypertension, or required more than the median number of antihypertensive drugs used in SPRINT. The easy-to-control BP group (n=18) comprised the remainder of the participants. A total of 60 differentially expressed genes were identified with a >2-fold change in the BP-difficult group. In BP-difficult participants, 2 of the most upregulated genes were associated with inflammation: Tumor Necrosis Factor Alpha Induced Protien 6 (fold change, 7.76; P=0.006) and Serpin Family B Member 9 (fold change, 5.10; P=0.007). Biological pathway analysis revealed an overrepresentation of inflammatory networks, including interferon signaling, granulocyte adhesion and diapedesis, and Janus Kinase family kinases in the BP-difficult group (P<0.001). Conclusions We conclude that transcriptomes from cells shed in first-morning urine identify a gene expression profile in difficult-to-control hypertension that associates with renal inflammation.
Assuntos
Hipertensão , Nefrite , Humanos , Transcriptoma , Hipertensão/tratamento farmacológico , Pressão Sanguínea/fisiologia , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Nefrite/genética , Nefrite/complicações , Inflamação/complicaçõesRESUMO
Mutations in IFIH1 gene encoding viral RNA sensor MDA5 have been reported responsible for many interferonopathies, including Aicardi-Goutières syndrome (AGS) and monogenic lupus, however, the pathological link between IFIH1 mutations and various autoimmune symptoms remains unclear. Here, we generated transgenic mice expressing human MDA5 R779H mutant (R779H Tg), reported in AGS and monogenic lupus patient. Mice spontaneously developed myocarditis and nephritis with upregulation of type I IFNs in the major organs. R779H Tg Mavs-/- and R779H Tg Ifnar-/- showed no phenotypes, indicating direct MDA5-signaling pathway involvement. Rag-2 deficiency and bone marrow cells transfer from wild type to adult mice did not prevent myocarditis development, while mice with cardiomyocyte-specific expression of hMDA5 R779H showed cardiomegaly and high expression of inflammatory cytokines. Taken together, our study clarifies that type I IFNs production and chemokines from cardiomyocytes starts in neonatal period and is critical for the development of myocarditis. Activated lymphocytes and auto-antibodies exacerbate the pathogenesis but are dispensable for the onset.
Assuntos
Helicase IFIH1 Induzida por Interferon/genética , Miocardite , Nefrite , Animais , Doenças Autoimunes do Sistema Nervoso/genética , Humanos , Helicase IFIH1 Induzida por Interferon/metabolismo , Camundongos , Camundongos Transgênicos , Mutação , Miocardite/genética , Nefrite/genéticaRESUMO
Hypertension is a leading risk factor for stroke, heart disease, chronic kidney disease, vascular cognitive impairment, and Alzheimer's disease. Previous genetic studies have nominated hundreds of genes linked to hypertension, and renal and cognitive diseases. Some have been advanced as candidate genes by showing that they can alter blood pressure or renal and cerebral vascular function in knockout animals; however, final validation of the causal variants and underlying mechanisms has remained elusive. This review chronicles 40 years of work, from the initial identification of adducin (ADD) as an ACTIN-binding protein suggested to increase blood pressure in Milan hypertensive rats, to the discovery of a mutation in ADD1 as a candidate gene for hypertension in rats that were subsequently linked to hypertension in man. More recently, a recessive K572Q mutation in ADD3 was identified in Fawn-Hooded Hypertensive (FHH) and Milan Normotensive (MNS) rats that develop renal disease, which is absent in resistant strains. ADD3 dimerizes with ADD1 to form functional ADD protein. The mutation in ADD3 disrupts a critical ACTIN-binding site necessary for its interactions with actin and spectrin to regulate the cytoskeleton. Studies using Add3 KO and transgenic strains, as well as a genetic complementation study in FHH and MNS rats, confirmed that the K572Q mutation in ADD3 plays a causal role in altering the myogenic response and autoregulation of renal and cerebral blood flow, resulting in increased susceptibility to hypertension-induced renal disease and cerebral vascular and cognitive dysfunction.
Assuntos
Proteínas de Ligação a Calmodulina/genética , Predisposição Genética para Doença/genética , Hipertensão Renal/genética , Hipertensão/genética , Nefrite/genética , Medicina de Precisão/métodos , Animais , Pressão Sanguínea/genética , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Homeostase/genética , Humanos , Mutação , Medicina de Precisão/tendências , Ratos , Circulação Renal/genéticaRESUMO
PURPOSE: Diabetic nephropathy (DN), one of severe diabetic complications in the diabetes, is the main cause of end stage renal disease (ESRD). Notably, the currently available medications used to treat DN remain limited. Here, we determined whether berberine (BBR) could enhance the anti-diabetic nephropathy activities of metformin (Met) and explored its possible mechanisms. METHOD: The anti-diabetic nephropathy properties were systematically analyzed in the diabetic db/db mice treated with Met, BBR or with combination of Met and BBR. RESULTS: We found that both single Met and BBR treatments, and combination therapy could lower blood glucose, and ameliorate insulin resistance. The improvement of lipids metabolism by co-administration was more evident, as indicated by reduced serum cholesterol and less fat accumulation in the liver. Further, it was found that Met and BBR treatments, and co-administration could attenuate the progression of DN. However, anti-diabetic nephropathy activities of Met were enhanced when combined with BBR, as evidenced by improved renal function and histological abnormalities of diabetic kidney. Mechanistically, BBR enhanced renal-protective effects of Met primarily through potently promoting expression of Trib1, which subsequently downregulated the increased protein levels of CCAAT/enhancer binding protein α (C/EBPα), and eventually inhibited fatty synthesis proteins and nuclear factor kappa-B (NF-κB) signaling. CONCLUSION: Our data provide novel insight that co-administration of BBR and Met exerts a preferable activity of anti-diabetic nephropathy via collectively enhancing lipolysis and inhibiting inflammation. Combination therapy with these two drugs may provide an effective therapeutic strategy for the medical treatment of diabetic nephropathy.
Assuntos
Berberina/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/agonistas , Metformina/farmacologia , Nefrite/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Berberina/uso terapêutico , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/imunologia , Modelos Animais de Doenças , Progressão da Doença , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Masculino , Metformina/uso terapêutico , Camundongos , Nefrite/genética , Nefrite/imunologia , Nefrite/patologia , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Despite the mechanisms of central and peripheral tolerance, the mature B cell compartment contains cells reactive for self-antigen. How these cells are poised not to respond and the mechanisms that restrain B cell responses to low-affinity endogenous antigens are not fully understood. Here, we demonstrate a critical role for the glycan-binding protein galectin-9 in setting the threshold of B cell activation and that loss of this regulatory network is sufficient to drive spontaneous autoimmunity. We further demonstrate a critical role for galectin-9 in restraining not only conventional B-2 B cells, but also innate-like B-1a cells. We show that galectin-9-deficient mice have an expanded population of B-1a cells and increased titers of B-1a-derived autoantibodies. Mechanistically, we demonstrate that galectin-9 regulates BCR and distinct TLR responses in B-1a cells, but not B-1b cells, by regulating the interaction between BCR and TLRs with the regulatory molecules CD5 and CD180, respectively. In the absence of galectin-9, B-1a cells are more readily activated and secrete increased titers of autoantibodies that facilitate autoantigen delivery to the spleen, driving autoimmune responses.
Assuntos
Autoimunidade/genética , Linfócitos B/metabolismo , Galectinas/deficiência , Fatores Etários , Animais , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Camundongos , Nefrite/genética , Esplenomegalia/genéticaRESUMO
Aristolochic acid nephropathy (AAN) is a unique type of progressive renal interstitial fibrotic disease caused by prolonged exposure to aristolochic acids (AAs) through AA-containing herbal medicines or AA-tainted food. Despite decades of research and affecting millions of people around the world, the pathophysiology of AAN remains incompletely understood. In this study, we tested the potential causative role of mitochondrial dysfunction in AAN development. Our findings revealed AA exposure induces an exposure concentration and duration dependent lowering of adenosine triphosphate in both cultured human kidney and liver cells, highlighting an AA exposure effect on mitochondrial energy production in the kidney and liver, which both are highly metabolically active and energy-demanding organs. Analysis with liquid chromatography-tandem mass spectrometry coupled with stable isotope dilution method detected high levels of mutagenic 8-oxo-2'-deoxyguanosine and 7-(deoxyadenosine-N6-yl)-aristolactam adduct on mitochondrial DNA isolated from AA-treated cells, unmasking a potentially important causative, but previously unknown role of mitochondrial DNA mutation in the pathophysiology of AAN development.
Assuntos
Ácidos Aristolóquicos/efeitos adversos , Dano ao DNA , DNA Mitocondrial/genética , Rim/efeitos dos fármacos , Nefrite/induzido quimicamente , Fibrose , Células HEK293 , Humanos , Rim/metabolismo , Rim/patologia , Nefrite/genética , Nefrite/patologiaRESUMO
Recent studies suggested that DNA double-strand breaks (DSBs) were associated with the pathogenesis of chronic kidney disease (CKD). The purpose of this investigation was to determine the role of Sirtuin6 (Sirt6), a histone deacetylase related to DNA damage repair, in angiotensin (Ang) II-induced DNA DSBs and the cell injury of podocytes and explore the possible mechanism. Here we showed that an increase of DNA DSBs was accompanied by a reduction in Sirt6 expression in the glomeruli of patients with hypertensive nephropathy (HN). Similar results were found in rat kidneys infused with Ang II and in cultured podocytes stimulated with Ang II. Sirt6 overexpression inhibited Ang II-induced ROS generation and DNA DSBs, and thus served as a protection against Ang II-induced apoptosis in podocytes. Moreover, Sirt6 activation enhanced Nrf2 and HO-1 gene expressions in podocytes after Ang II treatment. Furthermore, Nrf2 knockdown could partly reverse the cytoprotective effects of Sirt6 activation. In conclusion, our observations demonstrated that the Sirt6-Nrf2-HO-1 pathway played a vital role in relieving Ang II-mediated oxidative DNA damage and podocyte injury.
Assuntos
Angiotensina II/metabolismo , Apoptose , Quebras de DNA de Cadeia Dupla , Heme Oxigenase-1/metabolismo , Hipertensão Renal/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Nefrite/metabolismo , Podócitos/metabolismo , Sirtuínas/metabolismo , Animais , Heme Oxigenase-1/genética , Humanos , Hipertensão Renal/genética , Hipertensão Renal/fisiopatologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Nefrite/genética , Nefrite/fisiopatologia , Podócitos/citologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Sirtuínas/genéticaRESUMO
Rat Thy-1 nephritis (Thy-1N) is an animal model of human mesangioproliferative glomerulonephritis (MsPGN), accompanied by glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) deposition. Although sublytic C5b-9 formed on GMC membrane could induce cell proliferation, the mechanism is still unclear. In this study, we first demonstrated that the level of SRY related HMG-BOX gene 9 (SOX9), general control nonderepressible 5 (GCN5), fibroblast growth factor 1 (FGF1) and platelet-derived growth factor α (PDGFα) was all elevated both in the renal tissues of Thy-1N rats (in vivo) and in the GMCs (in vitro) with sublytic C5b-9 stimulation. Then, we not only discovered that sublytic C5b-9 caused GMC proliferation through increasing SOX9, GCN5, FGF1 and PDGFα expression, but also proved that SOX9 and GCN5 formed a complex and combined with FGF1 and PDGFα promoters, leading to FGF1 and PDGFα gene transcription. More importantly, GCN5 could mediate SOX9 acetylation at lysine 62 (K62) to enhance SOX9 binding to FGF1 or PDGFα promoter and promote FGF1 or PDGFα synthesis and GMC proliferation. Besides, the experiments in vivo also showed that FGF1 and PDGFα expression, GMC proliferation and urinary protein secretion in Thy-1N rats were greatly reduced by silencing renal SOX9, GCN5, FGF1 or PDGFα gene. Furthermore, the renal tissues of MsPGN patients also exhibited positive expression of these genes mentioned above. Collectively, our findings indicate that GCN5, SOX9 and FGF1/PDGFα can form an axis and play an essential role in sublytic C5b-9-triggered GMC proliferation, which might provide a novel insight into the pathogenesis of Thy-1N and MsPGN.
Assuntos
Proliferação de Células/genética , Proliferação de Células/fisiologia , Complexo de Ataque à Membrana do Sistema Complemento/genética , Rim/fisiologia , Células Mesangiais/fisiologia , Nefrite/genética , Transcrição Gênica/genética , Acetilação , Animais , Linhagem Celular , Matriz Extracelular/genética , Fator 1 de Crescimento de Fibroblastos/genética , Humanos , Masculino , Fator de Crescimento Derivado de Plaquetas/genética , Regiões Promotoras Genéticas/genética , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição SOX9/genética , Antígenos Thy-1/genética , Fatores de Transcrição de p300-CBP/genéticaRESUMO
The abnormal growth of epithelium-like cells has been noticed in spontaneously hypertensive rats (SHRs) with hypertensive nephropathy. However, the characteristics of abnormal epithelium-like cells and their pathogenesis in hypertensive nephropathy are not fully understood. In the present study, we investigated the correlation of epithelium-like cells with glomerular injury, and the effects of early drug intervention with telmisartan, an anti-hypertensive drug, on the growth of epithelium-like cells. The results showed that the epithelium-like cells were obviously observed lining along the luminal surface of Bowman's capsule in glomeruli, significantly resulting in the atrophy of the glomerular tuft. Some of the epithelium-like cells strongly expressed proliferating cell nuclear antigen (PCNA) and vimentin, indicating active cellular proliferation. The incidence of epithelium-like cells varied from 13.6% to 54.4% of glomeruli in 48-week-old SHRs, and from 5.1% to 18.0% of glomeruli in age-matched Wistar-Kyoto (WKY) rats (P<0.01). The linear regression analysis further confirmed an obvious correlation between the incidence of epithelium-like cells and the glomerular injury. Moreover, early intervention with telmisartan could dramatically attenuate the progression of epithelium-like cells growth. However, no significant effect of telmisartan on the established epithelium-like cells was observed. Taken together, we demonstrated the involvement of abnormal epithelium-like cells growth in glomerular injury during hypertensive nephropathy in SHRs, and firstly showed the positive effects of the anti-hypertensive drug on the progression of epithelium-like cells growth.
Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão Renal/tratamento farmacológico , Hipertensão/tratamento farmacológico , Nefrite/tratamento farmacológico , Telmisartan/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Epitélio/efeitos dos fármacos , Humanos , Hipertensão/genética , Hipertensão/patologia , Hipertensão Renal/genética , Hipertensão Renal/patologia , Rim/efeitos dos fármacos , Rim/patologia , Nefrite/genética , Nefrite/patologia , Ratos , Ratos Endogâmicos SHRRESUMO
BACKGROUND: The pathophysiology of Henoch-Schönlein purpura (HSP) is still unclear, but several findings suggest that genetic factors may influence disease susceptibility. We aimed to perform a genome-wide association study (GWAS) in pediatric HSP patients with an emphasis on severe HSP nephritis. METHODS: The study included 46 HSP patients, 42 of whom had undergone kidney biopsy. Forty-nine pediatric patients with an inflammatory bowel disease (IBD) served as an autoimmune disease control group while Finnish bone marrow and blood donors represented the general reference population (n = 18,757). GWAS was performed for HSP and IBD samples in a case-control manner against the reference population. The analysis also included imputation of human leukocyte antigen (HLA) alleles. RESULTS: GWAS analysis in HSP revealed several polymorphisms from the HLA region that surpassed the genome-wide significance level. Three HLA class II alleles were also significantly more frequent in HSP than in the reference population: DQA1*01:01, DQB1*05:01, and DRB1*01:01. Haplotype DQA1*01:01/DQB1*05:01/DRB1*01:01 occurred in 43.5% of HSP patients, whereas its frequency was 8.2% in IBD patients and 15.0% in the reference population. HSP patients with this haplotype showed similar baseline clinical findings and outcome as HSP patients negative for the haplotype. In IBD patients, no polymorphism or HLA allele appeared significant at the genome-wide level. CONCLUSIONS: Our results suggest that haplotype DQA1*01:01/DQB1*05:01/DRB1*01:01 is associated with susceptibility to HSP, but not with the severity of the kidney involvement. These HLA associations did not occur in IBD patients, suggesting that they are specific to HSP and not related to susceptibility to autoimmune diseases in general.
Assuntos
Antígenos HLA-DQ/genética , Cadeias HLA-DRB1/genética , Vasculite por IgA , Doenças Inflamatórias Intestinais , Nefrite , Alelos , Criança , Finlândia , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Vasculite por IgA/genética , Nefrite/genéticaRESUMO
Is the oncogene MYC upregulated or hyperactive? In the majority of human cancers, finding agents that target c-MYC has proved difficult. Here we report specific bacterial effector molecules that inhibit cellular MYC (c-MYC) in human cells. We show that uropathogenic Escherichia coli (UPEC) degrade the c-MYC protein and attenuate MYC expression in both human cells and animal tissues. c-MYC protein was rapidly degraded by both cell-free bacterial lysates and the purified bacterial protease Lon. In mice, intravesical or peroral delivery of Lon protease delayed tumor progression and increased survival in MYC-dependent bladder and colon cancer models, respectively. These results suggest that bacteria have evolved strategies to control c-MYC tissue levels in the host and that the Lon protease shows promise for therapeutic targeting of c-MYC in cancer.
Assuntos
Neoplasias do Colo/patologia , Genes myc , Neoplasias da Bexiga Urinária/patologia , Escherichia coli Uropatogênica/enzimologia , Doença Aguda , Animais , Modelos Animais de Doenças , Infecções por Escherichia coli/patologia , Deleção de Genes , Camundongos , Nefrite/genéticaRESUMO
AIMS: Rhabdomyolysis-associated acute kidney injury (AKI) is life-threatening but effective treatments is lacking. Recently, fatty acid-binding protein 4 (FABP4) has been identified as a mediator of ischemic and toxic AKI through regulating endoplasmic reticulum (ER) stress in our previous studies. However, the role of FABP4 in rhabdomyolysis-induced AKI and extended organelle dysfunctions need to be explored and validated. MAIN METHODS: We firstly performed mRNA-seq and bioinformatic analysis to investigate the role of FABP4. The mouse model was established via injecting glycerol to FABP4 wild type (WT) and knockout (KO) mice. Blood biochemical, inflammatory and apoptotic parameters were measured and compared across groups. Representative pathways of ER stress and mitochondrial dysfunction were also detected and quantified. KEY FINDINGS: Comparing FABP4 WT and FABP4 KO model groups, FABP4 deficiency significantly attenuated renal dysfunction, by reducing serum creatinine (165.90 ± 15.61 µmol/L vs 35.5 ± 8.33 µmol/L, p < 0.0001) and blood urea nitrogen (89.78 ± 6.82 mmol/L vs 19.75 ± 5.97 mmol/L, p < 0.0001), and alleviating tubular injury scores. Inflammatory and apoptotic responses were alleviated by FABP4 genetic inhibition. Mechanistically, glycerol injection triggered ER stress characterized by activated IRE1, PERK, and ATF6 signaling pathways, and induced mitochondrial dysfunction supported by ultrastructural damage, energy metabolic derangement, and excessive mitochondrial fission (upregulated DRP1/downregulated OPA1). These two organelle dysfunctions were effectively relieved by FABP4 deficiency. SIGNIFICANCE: Taken together, genetic inhibition of FABP4 protected against rhabdomyolysis-induced AKI via reducing ER stress as well as mitochondrial dysfunction. FABP4 might act as a novel therapeutic target in rhabdomyolysis-induced AKI.
Assuntos
Injúria Renal Aguda/etiologia , Estresse do Retículo Endoplasmático/genética , Proteínas de Ligação a Ácido Graxo/genética , Mitocôndrias/patologia , Rabdomiólise/patologia , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/metabolismo , Injúria Renal Aguda/patologia , Animais , Apoptose/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Rim/patologia , Rim/fisiologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/genética , Nefrite/genética , Nefrite/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismoRESUMO
The NSUN2 gene encodes a tRNA cytosine methyltransferase that functions in the maturation of leucyl tRNA (Leu) (CAA) precursors, which is crucial for the anticodon-codon pairing and correct translation of mRNA. Biallelic loss of function variants in NSUN2 are known to cause moderate to severe intellectual disability. Microcephaly, postnatal growth retardation, and dysmorphic facial features are common complications in this genetic disorder, and delayed puberty is occasionally observed. Here, we report four individuals, two sets of siblings, with biallelic loss-of-function variants in the NSUN2 gene. The first set of siblings have compound heterozygous frameshift variants: c.546_547insCT, p.Met183Leufs*13; c.1583del, p.Pro528Hisfs*19, and the other siblings carry a homozygous frameshift variant: c.1269dup, p.Val424Cysfs*14. In addition to previously reported clinical features, the first set of siblings showed novel complications of juvenile cataract and chronic nephritis. The other siblings showed hypomyelination and simplified gyral pattern in neuroimaging. NSUN2-related intellectual disability is a very rare condition, and less than 20 cases have been reported previously. Juvenile cataract, chronic nephritis, and brain anomaly shown in the present patients have not been previously described. Our report suggests clinical diversity of NSUN2-related intellectual disability.
Assuntos
Catarata/diagnóstico , Deficiência Intelectual/diagnóstico , Metiltransferases/genética , Nefrite/diagnóstico , Adolescente , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Catarata/complicações , Catarata/genética , Catarata/patologia , Criança , Pré-Escolar , Feminino , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Nefrite/complicações , Nefrite/genética , Nefrite/patologia , FenótipoRESUMO
The prevalence of chronic kidney disease is increasing globally; however, effective therapeutic options are limited. In this study, we aimed to identify urinary miRNAs reflecting the effect of therapeutic intervention in rats with comorbid hypertension and diabetes. Additionally, the potential beneficial effects of anti-platelet sarpogrelate and cilostazol were investigated. Nephropathy progression in streptozotocin (STZ)-treated spontaneously hypertensive rats (SHRs), including albuminuria, collagen deposition, and histopathological changes, was alleviated by sarpogrelate and antihypertensive agent telmisartan. Global analysis of urinary miRNAs identified that miR-199a-3p was commonly reduced by sarpogrelate and telmisartan treatment. In vitro analysis suggested CD151 as a target gene of miR-199a-3p: miR-199a-3p overexpression repressed CD151 levels and miR-199a-3p interacted with the 3'-untranslated region of the CD151 gene. In addition, we demonstrated that the miR-199a-3p/CD151 axis is associated with the transforming growth factor-ß1 (TGF-ß1)-induced fibrogenic pathway. TGF-ß1 treatment led to miR-199a-3p elevation and CD151 suppression, and miR-199a-3p overexpression or CD151-silencing enhanced TGF-ß1-inducible collagen IV and α-smooth muscle actin (α-SMA) levels. In vivo analysis showed that the decrease in CD151 and the increase in collagen IV and α-SMA in the kidney from STZ-treated SHR were restored by sarpogrelate and telmisartan administration. In an additional animal experiment using cilostazol and telmisartan, there was a correlation between urinary miR-199a-3p reduction and the ameliorating effects of cilostazol or combination with telmisartan. Collectively, these results indicate that urinary miR-199a-3p might be utilized as a marker for nephropathy treatment. We also provide evidence of the benefits of antiplatelet sarpogrelate and cilostazol in nephropathy progression.