Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
Thromb Haemost. 2012 Dec;108(6):1141-53. doi: 10.1160/TH12-07-0460. Epub 2012 Sep 26.
Coagulation and complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and complement activation, in part through discrete domains. TM's lectin like domain dampens complement activation, while its EGF-like domains independently enhance activation of the anti-coagulant and cytoprotective serine protease protein C (PC). A protective effect of activated PC in diabetic nephropathy is established. We hypothesised that TM controls diabetic nephropathy independent of PC through its lectin-like domain by regulating complement. Diabetic nephropathy was analysed in mice lacking TM's lectin-like domain (TMLeD/LeD) and controls (TMwt/wt). Albuminuria (290 μg/mg vs. 166 μg/mg, p=0.03) and other indices of experimental diabetic nephropathy were aggravated in diabetic TMLeD/LeD mice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TMLeD/LeD mice. Complement inhibition with enoxaparin ameliorated diabetic nephropathy in TMLeD/LeD mice (e.g. albuminuria 85 μg/mg vs. 290 μg/mg, p<0.001). In vitro TM's lectin-like domain cell-autonomously prevented glucose-induced complement activation on endothelial cells and - notably - on podocytes. Podocyte injury, which was enhanced in diabetic TMLeD/LeD mice, was reduced following complement inhibition with enoxaparin. The current study identifies a novel mechanism regulating complement activation in diabetic nephropathy. TM's lectin-like domain constrains glucose-induced complement activation on endothelial cells and podocytes and ameliorates albuminuria and glomerular damage in mice.
凝血和补体调节因子属于两个相互作用的系统，构成了糖尿病肾病的新兴机制。血栓调节蛋白（TM）调节凝血和补体激活，部分通过离散结构域。TM 的凝集素样结构域抑制补体激活，而其 EGF 样结构域独立增强抗凝血和细胞保护丝氨酸蛋白酶蛋白 C（PC）的激活。激活的 PC 在糖尿病肾病中的保护作用已得到证实。我们假设 TM 通过其凝集素样结构域调节补体，独立于 PC 控制糖尿病肾病。分析缺乏 TM 凝集素样结构域（TMLeD/LeD）的小鼠和对照（TMwt/wt）的糖尿病肾病。糖尿病 TMLeD/LeD 小鼠的蛋白尿（290 μg/mg 比 166 μg/mg，p=0.03）和其他实验性糖尿病肾病指标加重。糖尿病 TMLeD/LeD 小鼠肾小球中补体沉积（C3 和 C5b-9）明显增加。用依诺肝素抑制补体可改善 TMLeD/LeD 小鼠的糖尿病肾病（例如，蛋白尿 85 μg/mg 比 290 μg/mg，p<0.001）。体外实验中，TM 的凝集素样结构域自主地防止了内皮细胞和足细胞上葡萄糖诱导的补体激活，特别是足细胞。糖尿病 TMLeD/LeD 小鼠中足细胞损伤增加，用依诺肝素抑制补体后减少。本研究确定了一种调节糖尿病肾病中补体激活的新机制。TM 的凝集素样结构域限制了内皮细胞和足细胞上葡萄糖诱导的补体激活，并改善了小鼠的蛋白尿和肾小球损伤。
