高血压相关的菌群失调与几种临床并发症有关,包括炎症和可能的肾功能障碍。高血压期间的炎症和TLR4激活是由肠道生态失调相关的肠道完整性损害引起的。然而,TLR4在高血压引起的肠道菌群失调期间肾功能不全中的作用尚不清楚.我们设计了这项研究,通过利用TLR4正常(TLR4N)和TLR4突变(TLR4M)小鼠来解决这一知识空白。这些小鼠被输注高剂量的血管紧张素-II4周以诱发高血压。结果表明Ang-II显著增加肾动脉阻力指数(RI),肾血管减少,与TLR4M相比,TLR4N小鼠的肾功能(GFR)。肠道微生物组的16SrRNA测序分析显示,Ang-II诱导的高血压导致TLR4N和TLR4M小鼠肠道中Firmicutes:拟杆菌比例的改变;然而,这并不是相当不同的。此外,Ang-II-高血压降低了紧密连接蛋白的表达并增加了肠道通透性,在TLR4N小鼠中比在TLR4M小鼠中更突出。伴随着肠道高通透性,与TLR4N+生理盐水相比,在接受Ang-II治疗的TLR4N小鼠中观察到细菌成分向肾脏的易位增加.有趣的是,在Ang-II高血压TLR4M小鼠中,微生物群易位得到缓解。此外,Ang-II改变炎症的表达(IL-1β,IL-6)和抗炎IL-10)标志物,和细胞外基质蛋白,包括TLR4N小鼠肾脏中的MMP-2,-9,-14和TIMP-2,在TLR4M小鼠中钝化。我们的数据表明,TLR4的消融可以减轻高血压引起的肠道菌群失调,从而防止肠道通透性过高。细菌易位,减轻肾脏炎症和减轻肾功能障碍。
Hypertension-associated dysbiosis is linked to several clinical complications, including inflammation and possible kidney dysfunction. Inflammation and TLR4 activation during hypertension result from gut dysbiosis-related impairment of intestinal integrity. However, the contribution of TLR4 in kidney dysfunction during hypertension-induced gut dysbiosis is unclear. We designed this study to address this knowledge gap by utilizing TLR4 normal (TLR4N) and TLR4 mutant (TLR4M) mice. These mice were infused with high doses of Angiotensin-II for four weeks to induce hypertension. Results suggest that Ang-II significantly increased renal arterial resistive index (RI), decreased renal vascularity, and renal function (GFR) in TLR4N mice compared to TLR4M. 16 S rRNA sequencing analysis of gut microbiome revealed that Ang-II-induced hypertension resulted in alteration of Firmicutes: Bacteroidetes ratio in the gut of both TLR4N and TLR4M mice; however, it was not comparably rather differentially. Additionally, Ang-II-hypertension decreased the expression of tight junction proteins and increased gut permeability, which were more prominent in TLR4N mice than in TLR4M mice. Concomitant with gut hyperpermeability, an increased bacterial component translocation to the kidney was observed in TLR4N mice treated with Ang-II compared to TLR4N plus saline. Interestingly, microbiota translocation was mitigated in Ang-II-hypertensive TLR4M mice. Furthermore, Ang-II altered the expression of inflammatory (IL-1β, IL-6) and anti-inflammatory IL-10) markers, and extracellular matrix proteins, including MMP-2, -9, -14, and TIMP-2 in the kidney of TLR4N mice, which were blunted in TLR4M mice. Our data demonstrate that ablation of TLR4 attenuates hypertension-induced gut dysbiosis resulting in preventing gut hyperpermeability, bacterial translocation, mitigation of renal inflammation and alleviation of kidney dysfunction.