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1.
Nat Immunol ; 20(3): 254-256, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30742077
2.
Eur J Immunol ; 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30350853

RESUMO

Innate lymphoid cells (ILCs) represent a family of innate effector cells including NK cells, lymphoid tissue inducer (LTi) cells, and distinct ILC1, ILC2, and ILC3 subsets that produce IFN-γ, IL-5/IL-13, and IL-17A/IL-22, respectively. ILCs accumulate at mucosal sites and can promote the first-line defense against infection. ILCs are also implicated in tissue repair and can either pre-empt, or alternatively, exacerbate inflammation. Studies in mice have identified ILC precursors in fetal liver and adult BM that have diverse lineage potential. As such, these sites have been considered as the 'factories' to generate mature ILC. Here, we summarize knowledge concerning murine and human ILC development and discuss the recent identification of circulating multipotent and unipotent ILC precursors. We propose an alternative model of "ILC-poiesis", whereby blood ILC precursors migrate into tissues to complete their differentiation into mature ILC subsets under the influence of local environmental factors. Within this framework, ILC-poiesis guarantees appropriate ILC generation at the right place and the right time. We further discusss the potential applications of circulating ILC precursors for cell therapy of human disease.

3.
Nat Methods ; 15(8): 623-630, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30065364

RESUMO

Lymph nodes (LNs) facilitate the cellular interactions that orchestrate immune responses. Human immune system (HIS) mice are powerful tools for interrogation of human immunity but lack secondary lymphoid tissue (SLT) as a result of a deficiency in Il2rg-dependent lymphoid tissue inducer cells. To restore LN development, we induced expression of thymic-stromal-cell-derived lymphopoietin (TSLP) in a Balb/c Rag2-/-Il2rg-/-SirpaNOD (BRGS) HIS mouse model. The resulting BRGST HIS mice developed a full array of LNs with compartmentalized human B and T cells. Compared with BRGS HIS mice, BRGST HIS mice have a larger thymus, more mature B cells, and abundant IL-21-producing follicular helper T (TFH) cells, and show enhanced antigen-specific responses. Using BRGST HIS mice, we demonstrated that LN TFH cells are targets of acute HIV infection and represent a reservoir for latent HIV. In summary, BRGST HIS mice reflect the effects of SLT development on human immune responses and provide a model for visualization and interrogation of regulators of immunity.

4.
Sci Immunol ; 3(24)2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907691

RESUMO

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.

5.
Artigo em Inglês | MEDLINE | ID: mdl-29486229

RESUMO

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are major producers of the cytokines driving allergic asthma, and increased ILC2 numbers have been detected in blood and sputum of asthmatic patients. Asthma susceptibility has a strong genetic component, but the underlying mechanisms and whether asthma genetics affect ILC2 biology remain unclear. OBJECTIVE: We sought to study the ILC2 transcriptome and epigenome during airway inflammation (AI) to couple these to genes and genetic variants associated with asthma pathogenesis. METHODS: Mice harboring a reporter for the key ILC2 transcription factor GATA-3 were subjected to IL-33-driven AI, and ILC2s were isolated from bronchoalveolar lavage fluid and mediastinal lymph nodes. Human ILC2s were purified from peripheral blood and activated in vitro. We used RNA sequencing, genome-wide identification of histone-3 lysine-4 dimethylation-marked chromatin, and computational approaches to study the ILC2 transcriptome and epigenome. RESULTS: Activated ILC2s in mice displayed a tissue-specific gene expression signature that emerged from remarkably similar epigenomes. We identified superenhancers implicated in controlling ILC2 identity and asthma-associated genes. More than 300 asthma-associated genetic polymorphisms identified in genome-wide association studies localized to H3K4Me2+ gene regulatory elements in ILC2s. A refined set of candidate causal asthma-associated variants was uniquely enriched in ILC2, but not TH2 cell, regulatory regions. CONCLUSIONS: ILC2s in AI use a flexible epigenome that couples adaptation to new microenvironments with functional plasticity. Importantly, we reveal strong correlations between gene regulatory mechanisms in ILC2s and the genetic basis of asthma, supporting a pathogenic role for ILC2s in patients with allergic asthma.

6.
Oncotarget ; 8(47): 81729-81730, 2017 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-29137215
7.
Nat Commun ; 8(1): 1762, 2017 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-29176694

RESUMO

While patient selection and clinical management have reduced high-dose IL-2 (HDIL2) immunotherapy toxicities, the immune mechanisms that underlie HDIL2-induced morbidity remain unclear. Here we show that dose-dependent morbidity and mortality of IL-2 immunotherapy can be modeled in human immune system (HIS) mice. Depletion of human T cell subsets during the HDIL2 treatment reduces toxicity, pointing to the central function of T cells. Preferential expansion of effector T cells secondary to defective suppressive capacity of regulatory T (Treg) cells after HDIL2 therapy further underscores the importance of Treg in the maintenance of immune tolerance. IL-2 toxicity is induced by selective depletion or inhibition of Treg after LDIL2 therapy, and is ameliorated in HDIL2-treated HIS mice receiving the PIM-1 kinase inhibitor, Kaempferol. Modeling IL-2 pathophysiology in HIS mice offers a means to understand the functions of effector and regulatory T cells in immune-mediated toxicities associated with cancer immunotherapy.

8.
Curr Opin Immunol ; 44: 61-68, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28359987

RESUMO

Innate lymphoid cells (ILCs) are lineage- and antigen receptor-negative lymphocytes including natural killer (NK) cells and at least three distinguishable cell subsets (ILC1, ILC2, ILC3) that rapidly produce cytokines (IFN-γ, IL-5, IL-13, IL-17A, IL-22) upon activation. As such, ILCs can act as first-line defenders in the context of infection, inflammation and cancer. Because of the strong conservation between the expression of key transcription factors that can drive signature cytokine outputs in ILCs and differentiated helper T cells, it has been proposed that ILCs represent innate counterparts of the latter. Several distinct ILC precursors (ILCP) with pan-ILC (giving rise to all ILCs) or subset-restricted potentials have been described in both mouse and man. How and where these different ILCP give rise to more mature tissue-resident ILCs remains unclear. Recently, environmental signals have been shown to epigenetically influence canonical ILC differentiation pathways, generating substantial functional plasticity. These new results suggest that while ILC differentiation may be 'fixed' in principle, it remains 'flexible' in practice. A more comprehensive knowledge in the molecular mechanisms that regulate ILC development and effector functions may allow for therapeutic manipulation of ILCs for diverse disease conditions.


Assuntos
Imunoterapia , Inflamação/imunologia , Linfócitos/fisiologia , Células Progenitoras Linfoides/fisiologia , Neoplasias/imunologia , Animais , Diferenciação Celular , Plasticidade Celular , Citocinas/metabolismo , Epigênese Genética , Humanos , Imunidade Inata , Ativação Linfocitária , Camundongos , Linfócitos T Auxiliares-Indutores/fisiologia
9.
Cell ; 168(6): 1086-1100.e10, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28283063

RESUMO

Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCPs). How ILCPs give rise to mature tissue-resident ILCs remains unclear. Here, we identify circulating and tissue ILCPs in humans that fail to express the transcription factors and cytokine outputs of mature ILCs but have these signature loci in an epigenetically poised configuration. Human ILCPs robustly generate all ILC subsets in vitro and in vivo. While human ILCPs express low levels of retinoic acid receptor (RAR)-related orphan receptor C (RORC) transcripts, these cells are found in RORC-deficient patients and retain potential for EOMES+ natural killer (NK) cells, interferon gamma-positive (IFN-γ+) ILC1s, interleukin (IL)-13+ ILC2s, and for IL-22+, but not for IL-17A+ ILC3s. Our results support a model of tissue ILC differentiation ("ILC-poiesis"), whereby diverse ILC subsets are generated in situ from systemically distributed ILCPs in response to local environmental signals.


Assuntos
Linfócitos/citologia , Células-Tronco/citologia , Animais , Antígenos CD34/análise , Diferenciação Celular , Linhagem da Célula , Sangue Fetal/citologia , Feto/citologia , Humanos , Imunidade Inata , Interleucina-17 , Fígado/citologia , Pulmão/citologia , Linfócitos/imunologia , Tecido Linfoide/citologia , Camundongos , Proteínas Proto-Oncogênicas c-kit/análise , Transcrição Genética
10.
J Exp Med ; 213(4): 569-83, 2016 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-26976630

RESUMO

Group 2 innate lymphoid cells (ILC2) include IL-5- and IL-13-producing CRTh2(+)CD127(+)cells that are implicated in early protective immunity at mucosal surfaces. Whereas functional plasticity has been demonstrated for both human and mouse ILC3 subsets that can reversibly give rise to IFN-γ-producing ILC1, plasticity of human or mouse ILC2 has not been shown. Here, we analyze the phenotypic and functional heterogeneity of human peripheral blood ILC2. Although subsets of human CRTh2(+)ILC2 differentially express CD117 (c-kit receptor), some ILC2 surface phenotypes are unstable and can be modulated in vitro. Surprisingly, human IL-13(+)ILC2 can acquire the capacity to produce IFN-γ, thereby generating plastic ILC2. ILC2 cultures demonstrated that IFN-γ(+)ILC2 clones could be derived and were stably associated with increased T-BET expression. The inductive mechanism for ILC2 plasticity was mapped to the IL-12-IL-12R signaling pathway and was confirmed through analysis of patients with Mendelian susceptibility to mycobacterial disease due to IL-12Rß1 deficiencies that failed to generate plastic ILC2. We also detected IL-13(+)IFN-γ(+)ILC2 ex vivo in intestinal samples from Crohn's disease patients. These results demonstrate cytokine production plasticity for human ILC2 and further suggest that environmental cues can dictate ILC phenotype and function for these tissue-resident innate effector cells.


Assuntos
Doença de Crohn/imunologia , Imunidade Inata , Interleucina-12/imunologia , Intestinos/imunologia , Linfócitos/imunologia , Animais , Células Cultivadas , Doença de Crohn/patologia , Feminino , Humanos , Interferon gama/imunologia , Interleucina-13/imunologia , Interleucina-5/imunologia , Intestinos/patologia , Linfócitos/patologia , Masculino , Camundongos
11.
Inflamm Res ; 63(10): 831-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25063374

RESUMO

OBJECTIVE: Kidney injury molecule-1 (KIM-1) serves as a useful marker for monitoring tubular injury, and sustained KIM-1 expression may be implicated in chronic kidney fibrosis. In this study, we examine the kinetics and mechanisms of KIM-1 release in human proximal tubular epithelial cells (PTEC) under the activation by major pathologic players in diabetic nephropathy, including human serum albumin (HSA), glycated albumin (AGE-BSA) and high glucose. MATERIALS AND METHODS: The kinetics of KIM-1 release by PTEC under activation with HSA, AGE-BSA and high glucose, were determined by RT-PCR and ELISA. The activation profiles of major signaling pathways in PTEC were identified by PCR array. Based on the array data, blockade experiments were designed to assess their regulatory roles in KIM-1 release. RESULTS: Prompt shedding of KIM-1 was observed in PTEC cultured for 4 h with HSA and AGE-BSA, but not with high glucose. Culturing PTEC for 3 days with AGE-BSA exhibited sustained up-regulation of KIM-1 release, but not with HSA. In all culture experiments, high glucose did not induce KIM-1 release in PTEC. HSA and AGE-BSA activated multiple signaling pathways in PTEC including NFκB, ERK1/2 and the oxidative stress pathways. Long-term culturing PTEC with AGE-BSA but not HSA activated the Jak-Stat pathway. While incubation of PTEC with diphenylene iodonium blocked the short-term release of KIM-1 mediated by HSA or AGE-BSA, Jak-Stat inhibitors diminished the long-term KIM-1 release by PTEC induced by AGE-BSA. CONCLUSION: KIM-1 release in PTEC was differentially up-regulated by HSA and AGE-BSA. The short-term KIM-1 shedding was mediated by the reactive oxygen species, whereas Jak-Stat pathway regulates the long-term KIM-1 release.


Assuntos
Células Epiteliais/efeitos dos fármacos , Glucose/farmacologia , Produtos Finais de Glicação Avançada/farmacologia , Glicoproteínas de Membrana/metabolismo , Receptores Virais/metabolismo , Soroalbumina Bovina/farmacologia , Albumina Sérica/farmacologia , Células Cultivadas , Células Epiteliais/metabolismo , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Janus Quinases/metabolismo , Túbulos Renais Proximais/citologia , Cinética , Metaloproteinase 3 da Matriz/metabolismo , Glicoproteínas de Membrana/genética , Espécies Reativas de Oxigênio/metabolismo , Receptores Virais/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
12.
Immunol Cell Biol ; 92(5): 427-35, 2014 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24418819

RESUMO

Protein overload activates proximal tubule epithelial cells (PTECs) to release chemokines. Bone morphogenetic protein-7 (BMP-7) reduces infiltrating cells and tissue damage in acute and chronic renal injuries. The present study examines the inhibitory effect and related molecular mechanism of BMP-7 on chemokine and adhesion molecule synthesis by PTECs activated with human serum albumin (HSA). The expression profiles of chemokines and adhesion molecules in cultured human PTECs were screened by PCR array. Expression of CXCL1, CXCL2 and vascular cell adhesion protein 1 (VCAM-1) by PTECs was significantly upregulated by HSA and reduced by BMP-7. HSA activated both the canonical and noncanonical nuclear factor (NF)-κB pathways in PTECs, as indicated by the increased nuclear translocation of NF-κB p50 and p52 subunits. The nuclear translocation of NF-κB p52 was completely abrogated by BMP-7, whereas NF-κB p50 activation was only partially repressed. BMP-7 increased the expression of cellular inhibitor of apoptosis 1 (cIAP1), tumor necrosis factor receptor-associated factor (TRAF)2 and TRAF3, but not of NF-κB-inducing kinase (NIK) that was significantly upregulated by HSA. Silencing NIK recapitulated the partial inhibitory effect on HSA-induced chemokine synthesis by BMP-7. Complete abolishment of the chemokine synthesis was only achieved by including additional blockade of the NF-κB p65 translocation on top of NIK silencing. Our data suggest that BMP-7 represses the NIK-dependent chemokine synthesis in PTECs activated with HSA through blocking the noncanonical NF-κB pathway and partially interfering with the canonical NF-κB pathway.


Assuntos
Proteína Morfogenética Óssea 7/metabolismo , Quimiocinas/biossíntese , Células Epiteliais/metabolismo , Túbulos Renais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Células Cultivadas , Quimiocinas/genética , Regulação da Expressão Gênica , Humanos , Espaço Intracelular , Estabilidade Proteica , Transporte Proteico , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais
13.
J Cell Physiol ; 228(5): 917-24, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23086807

RESUMO

Regardless of the original causes and etiology, the progression to renal function declines follows a final common pathway associated with tubulointerstitial injury, in which the proximal tubular epithelial cells (PTEC) are instrumental. Kidney injury molecule-1 (KIM-1) is an emerging biomarker, and its expression and release are induced in PTEC upon injury. KIM-1 plays the role as a double-edged sword and implicates in the process of kidney injury and healing. Expression of KIM-1 is also associated with tubulointerstitial inflammation and fibrosis. More importantly, KIM-1 expressing PTEC play the role as the residential phagocytes, contribute to the removal of apoptotic cells and facilitate the regeneration of injured tubules. The precise mechanism of KIM-1 and its sheded ectodomain on restoration of tubular integrity after injury is not fully understood. Other than PTEC, macrophages (Mø) also implicate in tubular repair. Understanding the crosstalk between Mø and the injured PTEC is essential for designing appropriate methods for controlling the sophisticated machinery in tubular regeneration and healing. This article will review the current findings of KIM-1, beginning with its basic structure, utility as a biomarker, and possible functions, with focus on the role of KIM-1 in regeneration and healing of injured PTEC.


Assuntos
Nefropatias , Túbulos Renais Proximais , Glicoproteínas de Membrana/metabolismo , Receptores Virais/metabolismo , Ferimentos e Lesões/metabolismo , Biomarcadores/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Inflamação/metabolismo , Inflamação/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Glicoproteínas de Membrana/química , Fagócitos/metabolismo , Receptores Virais/química , Regeneração , Cicatrização
14.
Int J Biochem Cell Biol ; 44(6): 1040-50, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22484054

RESUMO

Tubulointerstitial injury is a common pathway in progressive renal impairment and human proximal tubular epithelial cells (PTEC) play a crucial role in this process. Kidney injury molecule-1 (KIM-1) has received increasing attention due to its potential utility as the therapeutic target and biomarker for kidney injury. This study aims to explore the underlying mechanism regulating the release of KIM-1. Cultured primary human PTEC expressed and released KIM-1 from the apical surface through an ectodomain shedding process mediated by matrix metalloproteinase (MMP), independent of gene expression and protein synthesis. The constitutive KIM-1 shedding by PTEC was enhanced in a dose- and time-dependent manner by human serum albumin (HSA) or tumor necrosis factor-α (TNF-α), two important physiological stimuli found during kidney injury. Data from PCR array screening of MMPs gene expression in PTEC following activation by HSA or TNF-α, and from blocking experiments using either synthetic MMP inhibitors or MMP gene knockdown by siRNA, revealed that the constitutive and accelerated shedding of KIM-1 in cultured PTEC was mediated by MMP-3. Furthermore, the up-regulation of MMP-3 and KIM-1 release by PTEC was associated with generation of reactive oxygen species. In a mouse model of acute kidney injury induced by ischemia and reperfusion, increased expression of MMP-3 and KIM-1 as well as their co-localization were observed in kidney from ischemic but not in sham-operated mice. Taken together, these in vitro and in vivo evidences suggest that MMP-3 plays an inductive role in KIM-1 shedding by PTEC.


Assuntos
Túbulos Renais Proximais/enzimologia , Metaloproteinase 3 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Animais , Western Blotting , Inativação Gênica , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Imuno-Histoquímica , Túbulos Renais Proximais/citologia , Camundongos , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real
15.
Nephrol Dial Transplant ; 27(8): 3119-29, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22287654

RESUMO

BACKGROUND: In peritoneal dialysis (PD), the peritoneal membrane exhibits structural and functional changes following continuous exposure to the non-physiological peritoneal dialysis fluid (PDF). In this study, we examined the effect of PDF on peritoneal adipose tissue in a diabetic milieu. METHODS: Six-week-old db/db mice and their non-diabetic littermates (db/m) were subjected to uninephrectomy. All animals then received intra-abdominal infusion of lactated Ringer's solution (Ringer) or 1.5% glucose-containing PDF (Dianeal) twice daily. Mice were sacrificed 4 weeks later. Parietal and visceral adipose tissues were harvested for examining gene and protein expression of adiponectin, leptin, monocyte chemotactic protein-1, vascular endothelial growth factor, tumor necrosis factor alpha (TNF-α), transforming growth factor beta and interleukin 6 (IL-6). Expression of TNF-α and F4/80+ macrophage accumulation in adipose tissues was assessed by immunohistochemical staining. Modulation of leptin synthesis and leptin receptors expression and the relevant signaling pathways were also determined by quantitative reverse transcription-polymerase chain reaction, immunoblotting or enzyme-linked immunosorbent assay. RESULTS: Compared to Ringer infusion, Dianeal infusion significantly increased serum leptin but decreased adiponectin in db/db mice. Increased expression of leptin, TNF-α and IL-6 was observed in visceral but not in parietal adipose tissue. Dianeal infusion also increased F4/80+ macrophage accumulation and enhanced the expression of pro-inflammatory cytokines including IL-6 and TNF-α in the visceral adipose tissue. Compared to db/m mice, infusion with Dianeal exhibited a more deleterious effect on db/db mice, characterized by an upregulation of short-form leptin receptor ObRa and activation of the mitogen-activated protein kinase signaling pathway. CONCLUSION: In conclusion, PD-induced hyperleptinemia amplifies the inflammatory response of adipose tissue through short-form leptin receptor when the long-form isotype is defective.


Assuntos
Soluções para Diálise/efeitos adversos , Leptina/metabolismo , Diálise Peritoneal Ambulatorial Contínua/efeitos adversos , Receptores para Leptina/metabolismo , Adipócitos/metabolismo , Adipocinas/sangue , Adipocinas/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Sequência de Bases , Primers do DNA/genética , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Inflamação/etiologia , Inflamação/metabolismo , Interleucina-6/metabolismo , Leptina/sangue , Leptina/genética , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
J Transl Med ; 9: 169, 2011 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-21974877

RESUMO

BACKGROUND: Inhibition of the renin-angiotensin-aldosterone system (RAAS) slows down the progression of chronic renal diseases (CKD) including IgA nephropathy (IgAN). Herein, we studied the pathogenetic roles of aldosterone (Aldo) in IgAN. METHODS: Human mesangial cells (HMC) was activated with polymeric IgA (pIgA) from IgAN patients and the effects on the expression of RAAS components and TGF-ß synthesis examined. To study the roles of RAAS in the glomerulotubular communication, proximal tubular epithelial cells (PTEC) was cultured with conditioned medium from pIgA-activated HMC with eplerenone or PD123319, the associated apoptotic event was measured by the generation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS). RESULTS: Polymeric IgA up-regulated the Aldo synthesis and aldosterone synthase expression by HMC. The release of TGF-ß by HMC was up-regulated synergistically by AngII and Aldo and this was inhibited by incubation of HMC with losartan plus eplerenone. Cultured PTEC express the mineralocorticoid receptor, but not synthesizing aldosterone. Apoptosis, demonstrated by cleaved PARP expression and caspase 3 activity, was induced in PTEC activated by conditioned medium prepared from HMC cultured with pIgA from IgAN patients. This apoptotic event was associated with increased generation of NADPH oxidase and ROS. Pre-incubation of PTEC with PD123319 and eplerenone achieved complete inhibition of PTEC apoptosis. CONCLUSIONS: Our data suggest that AngII and Aldo, released by pIgA activated HMC, served as mediators for inducing apoptosis of PTEC in glomerulo-tubular communications. Crosstalk between AngII and Aldo could participate in determining the tubular pathology of IgAN.


Assuntos
Aldosterona/farmacologia , Angiotensina II/farmacologia , Células Epiteliais/patologia , Glomerulonefrite por IGA/patologia , Túbulos Renais Proximais/patologia , Estresse Oxidativo/efeitos dos fármacos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Angiotensina II/metabolismo , Apoptose/efeitos dos fármacos , Células Cultivadas , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glomerulonefrite por IGA/enzimologia , Humanos , Imunoglobulina A/farmacologia , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/enzimologia , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Fatores de Tempo , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima/efeitos dos fármacos
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