Medical/Steno Aarhus Research Laboratory, Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.
Department of Internal Medicine, Regional Hospital Gødstrup, 7400 Herning, Denmark.
Int J Mol Sci. 2024 Jun 29;25(13):7204. doi: 10.3390/ijms25137204.
Autoreactivity of the complement system may escalate the development of diabetic nephropathy. We used the BTBR OB mouse model of type 2 diabetes to investigate the role of the complement factor mannan-binding lectin (MBL) in diabetic nephropathy. Female BTBR OB mice ( = 30) and BTBR non-diabetic WT mice ( = 30) were included. Plasma samples (weeks 12 and 21) and urine samples (week 19) were analyzed for MBL, C3, C3-fragments, SAA3, and markers for renal function. Renal tissue sections were analyzed for fibrosis, inflammation, and complement deposition. The renal cortex was analyzed for gene expression (complement, inflammation, and fibrosis), and isolated glomerular cells were investigated for MBL protein. Human vascular endothelial cells cultured under normo- and hyperglycemic conditions were analyzed by flow cytometry. We found that the OB mice had elevated plasma and urine concentrations of MBL-C ( < 0.0001 and < 0.001, respectively) and higher plasma C3 levels ( < 0.001) compared to WT mice. Renal cryosections from OB mice showed increased MBL-C and C4 deposition in the glomeruli and increased macrophage infiltration ( = 0.002). Isolated glomeruli revealed significantly higher MBL protein levels ( < 0.001) compared to the OB and WT mice, and no renal MBL expression was detected. We report that chronic inflammation plays an important role in the development of DN through the binding of MBL to hyperglycemia-exposed renal cells.
补体系统的自身反应性可能会加剧糖尿病肾病的发展。我们使用 2 型糖尿病 BTBR OB 小鼠模型来研究补体因子甘露聚糖结合凝集素 (MBL) 在糖尿病肾病中的作用。纳入了雌性 BTBR OB 小鼠（n = 30）和 BTBR 非糖尿病 WT 小鼠（n = 30）。在第 12 周和第 21 周时分析血浆样本，在第 19 周时分析尿液样本，检测 MBL、C3、C3 片段、SAA3 和肾功能标志物。分析肾脏组织切片的纤维化、炎症和补体沉积情况。分析肾脏皮质的基因表达（补体、炎症和纤维化），并检测分离的肾小球细胞中的 MBL 蛋白。在正常血糖和高血糖条件下培养的人血管内皮细胞通过流式细胞术进行分析。我们发现，与 WT 小鼠相比，OB 小鼠的血浆和尿液中 MBL-C 的浓度升高（<0.0001 和 <0.001），血浆 C3 水平升高（<0.001）。OB 小鼠的肾脏冷冻切片显示肾小球中 MBL-C 和 C4 沉积增加，巨噬细胞浸润增加（=0.002）。与 OB 和 WT 小鼠相比，分离的肾小球中的 MBL 蛋白水平显著升高（<0.001），但未检测到肾脏 MBL 表达。我们报告称，慢性炎症通过 MBL 与高血糖暴露的肾脏细胞结合，在糖尿病肾病的发展中发挥重要作用。
