RESUMO
Clinical hypertension (HT) is associated with renal inflammation and elevated circulating levels of proinflammatory cytokines. Interleukin (IL)-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and plays a crucial role in inflammation. Inhibition of IL-1 may contribute to modulation of the Angiotensin II (Ang II)-induced HT response. The present study aimed to elucidate the effects of IL-1Ra and anti-IL-1ß antibody (01BSUR) on Ang II-induced renal injury. To determine the contribution of IL-1Ra to Ang II-induced renal inflammation, male wildtype (WT) and IL-1Ra-deficient (IL-1Ra-/-) mice were infused with Ang II (1000 ng/kg/min) using subcutaneous osmotic pump for 14 days. We checked renal function, histological change, and several mRNA expressions 14 days after infusion. Fourteen days after infusion, systolic blood pressure (197 ± 5 vs 169 ± 9 mmHg, P<0.05) in IL-1Ra-/- mice significantly increased compared with WT mice. Furthermore, on day 14 of Ang II infusion, plasma IL-6 was 5.9-fold higher in IL-1Ra-/- versus WT mice (P<0.001); renal preproendothelin-1 mRNA expression was also significantly higher in IL-1Ra-/- mice (P<0.05). In addition, renal histology revealed greater damage in IL-1Ra-/- mice compared with WT mice 14 days after infusion. Finally, we administrated 01BSUR to both IL-1Ra-/- and WT mice, and 01BSUR treatment decreased Ang II-induced HT and renal damage (glomerular injury and fibrosis of the tubulointerstitial area) in both IL-1Ra-/- and WT mice compared with IgG2a treatment. Inhibition of IL-1 decreased Ang II-induced HT and renal damage in both IL-1Ra-/- and WT mice, suggesting suppression of IL-1 may provide an additional strategy to protect against renal damage in hypertensive patients.
Assuntos
Anticorpos/farmacologia , Hipertensão/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/antagonistas & inibidores , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Angiotensina II , Animais , Pressão Sanguínea/efeitos dos fármacos , Bosentana/farmacologia , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina/farmacologia , Endotelina-1/metabolismo , Fibrose , Humanos , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1beta/metabolismo , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de SinaisRESUMO
BACKGROUND: Angiotensin II (Ang II) activates components of the inflammatory cascade, which promotes hypertension and development of abdominal aortic aneurysm (AAA). This study aimed to elucidate the effects of an IL-1 receptor antagonist (IL-1Ra) and an anti-IL-1ß antibody (01BSUR) on Ang II-induced AAA. METHODS AND RESULTS: Male wild-type (WT) and IL-1Ra-deficient (IL-1Ra-/-) mice were infused with Ang II (1000â¯ng/kg/min) using subcutaneous osmotic pumps for 28â¯days. Fourteen days post-infusion, both systolic blood pressure (SBP) (Ang II-treated IL-1Ra-/-:149⯱â¯2 vs. Ang II-treated WT:126⯱â¯3â¯mmâ¯Hg, pâ¯<â¯0.001) and abdominal aortic width (0.94⯱â¯0.09 vs. 0.49⯱â¯0.03â¯mm, pâ¯<â¯0.001) were significantly higher in IL-1Ra-/- mice than in WT mice. Because 28-day infusion with Ang II in IL-1Ra-/- mice significantly increased the occurrence of fatal aortic rupture (89% vs. 6%, pâ¯<â¯0.0001), both types of mice were infused with Ang II for only 14â¯days, and histological analyses were performed at 28â¯days. Interestingly, AAA increased more significantly in IL-1Ra-/- mice than in WT mice (pâ¯<â¯0.001), although SBP did not differ at 28â¯days in IL-1Ra-/- and WT mice (117⯱â¯4 vs. 115⯱â¯3â¯mmâ¯Hg, pâ¯=â¯0.71 (after cessation of Ang II infusion)). Histological analyses showed numerous inflammatory cells around the abdominal aorta in IL-1Ra-/- mice, but not in WT mice. Finally, compared with IgG2a treatment, treatment with 01BSUR decreased Ang II-induced AAA in IL-1Ra-/- mice. CONCLUSIONS: The present study demonstrates that inhibition of IL-1ß significantly suppresses AAA formation after Ang II infusion, suggesting that suppression of IL-1ß may provide an additional strategy to protect against AAA in hypertensive patients.
Assuntos
Angiotensina II/toxicidade , Aneurisma da Aorta Abdominal/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Vasculite/metabolismo , Animais , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/patologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Imunoglobulina G/farmacologia , Imunoglobulina G/uso terapêutico , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/antagonistas & inibidores , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vasculite/induzido quimicamente , Vasculite/patologiaRESUMO
IκBNS is a nuclear IκB protein which negatively regulates nuclear factor-κB activity. We demonstrated that IκBNS deficiency accelerates atherosclerosis in LDL receptor-deficient (LDLr-/-) mice via increased interleukin (IL)-6 production by macrophages. Previous studies showed that the increase in IL-6 might contribute to the development of atherosclerotic lesions. However, whether an anti-mouse IL-6 receptor antibody (MR16-1) can protect atherosclerotic lesions in atherogenic mice remains to be elucidated. We investigated atherosclerotic lesions in LDLr-/- and IκBNS-/-/LDLr-/- mice after 16 weeks consumption of a high-fat diet. All mice received intraperitoneal injections of MR16-1 or phosphate-buffered saline (PBS) (control) once a week during a high-fat diet consumption. Treatment of MR16-1 yielded no adverse systemic effects, and we detected no significant differences in serum cholesterol levels in either group. The atherosclerotic lesions were significantly increased in IκBNS-/-/LDLr-/- compared with LDLr-/- mice (p < 0.01) under treatment of PBS. However, MR16-1 treatment abolished the significant difference of atherosclerotic lesions between IκBNS-/-/LDLr-/- and LDLr-/- mice. Interestingly, MR16-1 also significantly decreased atherosclerotic lesions in LDLr-/- mice compared with PBS treatment (p < 0.05). Immunostaining revealed percent phospho-STAT3-positive cell were significantly decreased in the atherosclerotic lesions of MR16-1 treated both IκBNS-/-/LDLr-/- and LDLr-/- mice compared with PBS-treated mice, indicating MR16-1 could suppress atherosclerotic lesions via the inhibition of IL-6-STAT3 signaling pathway. This study highlights the potential therapeutic benefit of anti-IL-6 therapy in preventing atherogenesis induced by dyslipidemia and/or inflammation.