RESUMO
Janus-activated kinase (JAKs)-signal transducer and activator of transcription 3 (STAT-3) signalling play critical roles in immunoregulation and immunopathology, which involve inflammatory responses and enteritis. JAK phosphorylates STAT-3 in response to stimulation by cytokines or growth factors, and then activates or represses the gene expression. STAT-3 is activated persistently in cancer cells and contributes to the malignant progression of various types of cancer and inflammation. To elucidate the different roles of JAKs in the activation of STAT-3, the lipopolysaccharide-induced primary intestinal epithelial cell (IEC) acute inflammatory model was established. Small interference RNAs (siRNAs) were then employed to attenuate the expression levels of JAKs. Real-time quantitative reverse transcription-polymerase chain reaction (PCR) (qRT-PCR) revealed that JAK mRNA levels were reduced efficiently by JAK-specific siRNAs. Under the IEC inflammatory model transfected with si-JAK, which equates to effective silencing, qRT-PCR and Western blot assays, suggested that knockdowns of JAK attenuated the JAK-induced down-regulation of STAT-3 at the mRNA or protein levels. In particular, JAK1 played a key role, which was consistent with the RNA-Seq results. Subsequently, the expression levels of proinflammatory cytokines interleukin (IL)-1ß and tumour necrosis factor (TNF)-α were down-regulated in the IEC inflammatory model transfected with si-JAK1. JAK1 appears as a direct activator for STAT-3, whereas treatments targeting JAK1 repressed STAT-3 sufficiently pathways in the IEC inflammatory model. Therefore, the control of JAK1 using siRNAs has the potential to be an effective strategy against enteritis.
Assuntos
Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/imunologia , Proteínas Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Células Epiteliais , Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas Quinases/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Coelhos , Fator de Transcrição STAT3/genéticaRESUMO
BACKGROUND: Patients with atherosclerotic cardio-cerebrovascular disease are at high risk of kidney dysfunction because of the overlap of several risk factors. The purpose of this study is to examine the prevalence and characteristics and risk factors for kidney dysfunction in the cardio-cerebrovascular disease population. METHODS: Renal functions of 1012 patients with the cardio-cerebrovascular disease were evaluated with the purpose of evaluating characteristics of the incidence, risk factors for kidney dysfunction in the cardio-cerebrovascular disease population. RESULTS: In the univariate analysis, the major risk factors for kidney dysfunction in the patients with the cardio-cerebrovascular disease were age, gender, hypertension, diabetes mellitus, dyslipidemia and serum uric acid. In the patients with both hypertension and diabetes mellitus the percentages of significantly decreased eGFR were 25.6%. Results of multivariable analysis showed that diabetes mellitus (odds ratio (OR) 1.609, 95% confidence intervals (CI) 1.08-2.398, P = 0.019), hypertension (OR 1.547, 95% CI 1.049-2.281, P = 0.028) and serum uric acid (OR 1.009, 95% CI 1.007-1.010, P < 0.001) were independent risk factors for reduced kidney function. CONCLUSIONS: In the context of the cardio-cerebrovascular disease kidney dysfunction is common and has a high prevalence. Patients with both cardio-cerebrovascular disease and kidney dysfunction at any stage should be recognized as high-risk population.
