Boudhabhay Idris, Poillerat Victoria, Grunenwald Anne, Torset Carine, Leon Juliette, Daugan Marie V, Lucibello Francesca, El Karoui Khalil, Ydee Amandine, Chauvet Sophie, Girardie Patrick, Sacks Steven, Farrar Conrad A, Garred Peter, Berthaud Romain, Le Quintrec Moglie, Rabant Marion, de Lonlay Pascale, Rambaud Caroline, Gnemmi Viviane, Fremeaux-Bacchi Veronique, Frimat Marie, Roumenina Lubka T
Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France.
Institut National de la Santé et de la Recherche Médicale U932, Paris Sciences et Lettres University, Institut Curie, Paris, France.
Kidney Int. 2021 Mar;99(3):581-597. doi: 10.1016/j.kint.2020.09.033. Epub 2020 Nov 1.
Rhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury is lacking and the mechanisms of the injury are unclear. To clarify this, we studied intra-kidney complement activation (C3d and C5b-9 deposits) in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. The lectin complement pathway was found to be activated in the kidney, likely via an abnormal pattern of Fut2-dependent cell fucosylation, recognized by the pattern recognition molecule collectin-11 and this proceeded in a C4-independent, bypass manner. Concomitantly, myoglobin-derived heme activated the alternative pathway. Complement deposition and acute kidney injury were attenuated by pre-treatment with the heme scavenger hemopexin. This indicates that complement was activated in a unique double-trigger mechanism, via the alternative and lectin pathways. The direct pathological role of complement was demonstrated by the preservation of kidney function in C3 knockout mice after the induction of rhabdomyolysis. The transcriptomic signature for rhabdomyolysis-induced acute kidney injury included a strong inflammatory and apoptotic component, which were C3/complement-dependent, as they were normalized in C3 knockout mice. The intra-kidney macrophage population expressed a complement-sensitive phenotype, overexpressing CD11b and C5aR1. Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. Hence, heme scavenging and complement inhibition represent promising therapeutic strategies.
横纹肌溶解症是一种危及生命的疾病，由骨骼肌损伤引起，急性肾损伤是主要并发症，会显著恶化预后。目前缺乏针对横纹肌溶解症所致急性肾损伤的特异性治疗方法，且损伤机制尚不清楚。为了阐明这一点，我们研究了横纹肌溶解症所致急性肾损伤患者和小鼠肾脏内肾小管和血管中的补体激活情况（C3d和C5b - 9沉积）。发现凝集素补体途径在肾脏中被激活，可能是通过Fut2依赖性细胞岩藻糖基化的异常模式，被模式识别分子collectin - 11识别，并且以不依赖C4的旁路方式进行。同时，肌红蛋白衍生的血红素激活了替代途径。用血红素清除剂血红素结合蛋白预处理可减轻补体沉积和急性肾损伤。这表明补体通过替代途径和凝集素途径以独特的双触发机制被激活。在诱导横纹肌溶解症后，C3基因敲除小鼠的肾功能得以保留，证明了补体的直接病理作用。横纹肌溶解症所致急性肾损伤的转录组特征包括强烈的炎症和凋亡成分，这些成分是C3/补体依赖性的，因为在C3基因敲除小鼠中它们恢复正常。肾脏内巨噬细胞群体表达补体敏感表型，过度表达CD11b和C5aR1。因此，我们的结果证明了血红素和补体在横纹肌溶解症所致急性肾损伤中的直接病理作用。因此，清除血红素和抑制补体代表了有前景的治疗策略。
