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白细胞介素-1β 抑制肥胖 2 型糖尿病小鼠的慢性肾脏病。

Interleukin-1β Inhibition for Chronic Kidney Disease in Obese Mice With Type 2 Diabetes.

机构信息

Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, Munich, Germany.

Division of Nephrology, Krankenhaus Harlaching, Munich, Germany.

出版信息

Front Immunol. 2019 May 29;10:1223. doi: 10.3389/fimmu.2019.01223. eCollection 2019.

Abstract

Inflammasome-driven release of interleukin(IL)-1β is a central element of many forms of sterile inflammation and has been evident to promote the onset and progression of diabetic kidney disease. We microdissected glomerular and tubulointerstitial samples from kidney biopsies of patients with diabetic kidney disease and found expression of IL-1β mRNA. Immunostaining of such kidney biopsies across a broad spectrum of diabetic kidney disease stages revealed IL-1β positivity in a small subset of infiltrating immune cell. Thus, we speculated on a potential of IL-1β as a therapeutic target and neutralizing the biological effects of murine IL-1β with a novel monoclonal antibody in uninephrectomized diabetic db/db mice with progressive type 2 diabetes- and obesity-related single nephron hyperfiltration, podocyte loss, proteinuria, and progressive decline of total glomerular filtration rate (GFR). At 18 weeks albuminuric mice were randomized to intraperitoneal injections with either anti-IL-1β or control IgG once weekly for 8 weeks. During this period, anti-IL-1β IgG had no effect on food or fluid intake, body weight, and fasting glucose levels. At week 26, anti-IL-1β IgG had reduced renal mRNA expression of kidney injury markers (Ngal) and fibrosis (Col1, a-Sma), significantly attenuated the progressive decline of GFR in hyperfiltrating diabetic mice, and preserved podocyte number without affecting albuminuria or indicators of single nephron hyperfiltration. No adverse effect were observed. Thus, IL-1β contributes to the progression of chronic kidney disease in type 2 diabetes and might therefore be a valuable therapeutic target, potentially in combination with drugs with different mechanisms-of-action such as RAS and SGLT2 inhibitors.

摘要

炎症小体驱动的白细胞介素(IL)-1β释放是多种形式的无菌性炎症的核心环节,已被证明可促进糖尿病肾病的发病和进展。我们从小鼠糖尿病肾病患者的肾活检组织中分离肾小球和肾小管间质样本,并发现了 IL-1β mRNA 的表达。对跨越广泛糖尿病肾病阶段的此类肾活检组织进行免疫染色显示,一小部分浸润免疫细胞呈 IL-1β阳性。因此,我们推测 IL-1β可能是一个有治疗潜力的靶点,并在进行性 2 型糖尿病和肥胖相关的单肾单位高滤过、足细胞丢失、蛋白尿和总肾小球滤过率(GFR)逐渐下降的单侧肾切除糖尿病 db/db 小鼠中,用一种新型单克隆抗体来中和鼠源 IL-1β的生物学效应。在 18 周时,白蛋白尿小鼠被随机分为两组,每周接受一次腹膜内注射抗 IL-1β 或对照 IgG,持续 8 周。在此期间,抗 IL-1β IgG 对食物或液体摄入、体重和空腹血糖水平没有影响。在第 26 周时,抗 IL-1β IgG 降低了高滤过糖尿病小鼠肾脏损伤标志物(Ngal)和纤维化(Col1、a-Sma)的 mRNA 表达,显著减轻了 GFR 的进行性下降,并保持了足细胞数量,而不影响蛋白尿或单肾单位高滤过的指标。未观察到不良反应。因此,IL-1β参与了 2 型糖尿病慢性肾脏病的进展,因此可能是一个有价值的治疗靶点,可能与具有不同作用机制的药物联合使用,如 RAS 和 SGLT2 抑制剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d68/6549251/937ac8eaf467/fimmu-10-01223-g0001.jpg

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