肠道细菌易位导致糖尿病肾病。
Intestinal Bacterial Translocation Contributes to Diabetic Kidney Disease.
机构信息
Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.
Division of Infection Control, Kanazawa University Hospital, Kanazawa, Japan.
出版信息
J Am Soc Nephrol. 2022 Jun;33(6):1105-1119. doi: 10.1681/ASN.2021060843. Epub 2022 Mar 9.
BACKGROUND
In recent years, many studies have focused on the intestinal environment to elucidate pathogenesis of various diseases, including kidney diseases. Impairment of the intestinal barrier function, the "leaky gut," reportedly contributes to pathologic processes in some disorders. Mitochondrial antiviral signaling protein (MAVS), a component of innate immunity, maintains intestinal integrity. The effects of disrupted intestinal homeostasis associated with MAVS signaling in diabetic kidney disease remains unclear.
METHODS
To evaluate the contribution of intestinal barrier impairment to kidney injury under diabetic conditions, we induced diabetic kidney disease in wild-type and MAVS knockout mice through unilateral nephrectomy and streptozotocin treatment. We then assessed effects on the kidney, intestinal injuries, and bacterial translocation.
RESULTS
MAVS knockout diabetic mice showed more severe glomerular and tubular injuries compared with wild-type diabetic mice. Owing to impaired intestinal integrity, the presence of intestine-derived and elevated IL-17 were detected in the circulation and kidneys of diabetic mice, especially in diabetic MAVS knockout mice. Stimulation of tubular epithelial cells with activated MAVS pathways and the phosphorylation of Stat3 and ERK1/2, leading to the production of kidney injury molecule-1 (KIM-1). Nevertheless, MAVS inhibition induced inflammation in the intestinal epithelial cells and KIM-1 production in tubular epithelial cells under supernatant or IL-17 stimulation. Treatment with neutralizing anti-IL-17 antibody treatment had renoprotective effects. In contrast, LPS administration accelerated kidney injury in the murine diabetic kidney disease model.
CONCLUSIONS
Impaired MAVS signaling both in the kidney and intestine contributes to the disrupted homeostasis, leading to diabetic kidney disease progression. Controlling intestinal homeostasis may offer a novel therapeutic approach for this condition.
背景
近年来，许多研究集中在肠道环境上，以阐明包括肾脏疾病在内的各种疾病的发病机制。据报道，肠道屏障功能的损伤（“漏肠”）导致了一些疾病的病理过程。线粒体抗病毒信号蛋白（MAVS）作为先天免疫的一部分，维持着肠道的完整性。MAVS 信号相关的肠道内稳态紊乱在糖尿病肾病中的作用尚不清楚。
方法
为了评估与 MAVS 信号相关的肠道屏障损伤对糖尿病条件下肾脏损伤的贡献，我们通过单侧肾切除术和链脲佐菌素处理诱导野生型和 MAVS 敲除小鼠发生糖尿病肾病。然后，我们评估了对肾脏、肠道损伤和细菌易位的影响。
结果
与野生型糖尿病小鼠相比，MAVS 敲除糖尿病小鼠的肾小球和肾小管损伤更为严重。由于肠道完整性受损，在循环和肾脏中检测到源自肠道的，并发现 IL-17 水平升高，尤其是在糖尿病 MAVS 敲除小鼠中。用 刺激肾小管上皮细胞可激活 MAVS 途径，并磷酸化 Stat3 和 ERK1/2，导致肾脏损伤分子-1（KIM-1）的产生。然而，在 上清液或 IL-17 刺激下，MAVS 抑制会诱导肠道上皮细胞炎症和肾小管上皮细胞 KIM-1 的产生。用中和抗 IL-17 抗体治疗具有肾脏保护作用。相反，LPS 给药加速了糖尿病肾病小鼠模型的肾脏损伤。
结论
肾脏和肠道中 MAVS 信号的受损均导致内稳态紊乱，从而导致糖尿病肾病的进展。控制肠道内稳态可能为这种疾病提供一种新的治疗方法。
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