Krishnan S M, Dowling J K, Ling Y H, Diep H, Chan C T, Ferens D, Kett M M, Pinar A, Samuel C S, Vinh A, Arumugam T V, Hewitson T D, Kemp-Harper B K, Robertson A A B, Cooper M A, Latz E, Mansell A, Sobey C G, Drummond G R
Department of Pharmacology, Monash University, Clayton, Vic., Australia.
Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Clayton, Vic., Australia.
Br J Pharmacol. 2016 Feb;173(4):752-65. doi: 10.1111/bph.13230. Epub 2015 Jul 31.
Inflammasomes are multimeric complexes that facilitate caspase-1-mediated processing of the pro-inflammatory cytokines IL-1β and IL-18. Clinical hypertension is associated with renal inflammation and elevated circulating levels of IL-1β and IL-18. Therefore, we investigated whether hypertension in mice is associated with increased expression and/or activation of the inflammasome in the kidney, and if inhibition of inflammasome activity reduces BP, markers of renal inflammation and fibrosis.
Wild-type and inflammasome-deficient ASC(-/-) mice were uninephrectomized and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt). Control mice were uninephrectomized but received a placebo pellet and water. BP was measured by tail cuff; renal expression of inflammasome subunits and inflammatory markers was measured by real-time PCR and immunoblotting; macrophage and collagen accumulation was assessed by immunohistochemistry.
1K/DOCA/salt-induced hypertension in mice was associated with increased renal mRNA expression of inflammasome subunits NLRP3, ASC and pro-caspase-1, and the cytokine, pro-IL-1β, as well as protein levels of active caspase-1 and mature IL-1β. Following treatment with 1K/DOCA/salt, ASC(-/-) mice displayed blunted pressor responses and were also protected from increases in renal expression of IL-6, IL-17A, CCL2, ICAM-1 and VCAM-1, and accumulation of macrophages and collagen. Finally, treatment with a novel inflammasome inhibitor, MCC950, reversed hypertension in 1K/DOCA/salt-treated mice.
Renal inflammation, fibrosis and elevated BP induced by 1K/DOCA/salt treatment are dependent on inflammasome activity, highlighting the inflammasome/IL-1β pathway as a potential therapeutic target in hypertension.
炎性小体是促进半胱天冬酶 -1介导的促炎细胞因子白细胞介素 -1β（IL-1β）和白细胞介素 -18（IL-18）加工的多聚体复合物。临床高血压与肾炎症以及循环中IL-1β和IL-18水平升高有关。因此，我们研究了小鼠高血压是否与肾脏中炎性小体表达增加和/或激活有关，以及抑制炎性小体活性是否能降低血压、肾脏炎症和纤维化标志物。
野生型和炎性小体缺陷的ASC（-/-）小鼠进行单侧肾切除，并给予醋酸脱氧皮质酮和生理盐水饮用（1K/DOCA/盐）。对照小鼠进行单侧肾切除，但接受安慰剂丸和水。通过尾套法测量血压；通过实时聚合酶链反应（PCR）和免疫印迹法测量炎性小体亚基和炎症标志物的肾脏表达；通过免疫组织化学评估巨噬细胞和胶原蛋白积累。
1K/DOCA/盐诱导的小鼠高血压与炎性小体亚基NLRP3、ASC和前半胱天冬酶 -1的肾脏mRNA表达增加有关，以及细胞因子前IL-1β，以及活性半胱天冬酶 -1和成熟IL-1β的蛋白质水平增加。用1K/DOCA/盐处理后，ASC（-/-）小鼠的升压反应减弱，并且还免受IL-6、IL-17A、CCL2、ICAM-1和VCAM-1肾脏表达增加以及巨噬细胞和胶原蛋白积累的影响。最后，用新型炎性小体抑制剂MCC950治疗可使1K/DOCA/盐处理的小鼠血压恢复正常。
1K/DOCA/盐处理诱导的肾脏炎症、纤维化和血压升高依赖于炎性小体活性，突出了炎性小体/IL-1β途径作为高血压潜在治疗靶点的重要性。
