Interleukin-1β Inhibition for Chronic Kidney Disease in Obese Mice With Type 2 Diabetes
Interleukin-1β Inhibition for Chronic Kidney Disease in Obese Mice With Type 2 Diabetes
复制标题
DOI：
10.3389/fimmu.2019.01223
复制
发表时间：
2019-05-29
影响因子：
7.3
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
--
作者：
Lei, Yutian;Devarapu, Satish K.;Anders, Hans-Joachim
炎性小体驱动的白细胞介素（IL）-1 β的释放是许多形式的无菌炎症的核心要素，并且已被证明促进糖尿病肾病的发作和进展。我们显微解剖了糖尿病肾病患者肾活检的肾小球和肾小管间质样本，发现IL-1 β mRNA表达。在广泛的糖尿病肾病阶段中，这种肾活检的免疫染色显示在浸润免疫细胞的一小部分中IL-β阳性。因此，我们推测IL-1 β作为治疗靶点的潜力，并在单侧肾切除的糖尿病db/db小鼠中用新型单克隆抗体中和鼠IL-1 β的生物学效应，这些小鼠具有进行性2型糖尿病和肥胖相关的单肾单位超滤、足细胞丢失、蛋白尿和总肾小球滤过率（GFR）进行性下降。在第18周，将白蛋白尿小鼠随机分配至腹膜内注射抗IL-1 β或对照IgG，每周一次，持续8周。在此期间，抗IL-1 β IgG对食物或液体摄入量、体重和空腹血糖水平没有影响。在第26周，抗IL-1 β IgG降低了肾损伤标志物（Ngal）和纤维化（Col 1，a-Sma）的肾mRNA表达，显著减弱了超滤糖尿病小鼠GFR的进行性下降，并保留了足细胞数量，而不影响白蛋白尿或单肾单位超滤指标。未观察到不良反应。因此，IL-1 β有助于2型糖尿病慢性肾脏疾病的进展，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（如RAS和SGLT 2抑制剂）联合使用。
Inflammasome-driven release of interleukin(IL)-1 beta 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-1 beta mRNA. Immunostaining of such kidney biopsies across a broad spectrum of diabetic kidney disease stages revealed IL-beta positivity in a small subset of infiltrating immune cell. Thus, we speculated on a potential of IL-1 beta as a therapeutic target and neutralizing the biological effects of murine IL-1 beta 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-1 beta or control IgG once weekly for 8 weeks. During this period, anti-IL-1 beta IgG had no effect on food or fluid intake, body weight, and fasting glucose levels. At week 26, anti-IL-1 beta 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-1 beta 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.