Division of Nephrology, Rheinisch-Westfälische Technische Hochschule (RWTH) University of Aachen , Aachen , Germany.
Division of Gastroenterology, Saarland University Medical Center , Homburg , Germany.
Am J Physiol Renal Physiol. 2018 Jan 1;314(1):F35-F46. doi: 10.1152/ajprenal.00060.2017. Epub 2017 Sep 13.
Complement factor C5a has two known receptors, C5aR, which mediates proinflammatory effects, and C5L2, a potential C5a decoy receptor. We previously identified C5a/C5aR signaling as a potent profibrotic pathway in the kidney. Here we tested for the first time the role of C5L2 in renal fibrosis. In unilateral ureteral obstruction (UUO)-induced kidney fibrosis, the expression of C5aR and C5L2 increased similarly and gradually as fibrosis progressed and was particularly prominent in injured dilated tubules. Genetic deficiency of either C5aR or C5L2 significantly reduced UUO-induced tubular injury. Expression of key proinflammatory mediators, however, significantly increased in C5L2- compared with C5aR-deficient mice, but this had no effect on the number of renal infiltrating macrophages or T cells. Moreover, in C5L2 mice, the cytokine and matrix metalloproteinase-inhibitor tissue inhibitor of matrix metalloproteinase-1 was specifically enhanced. Consequently, in C5L2 mice the degree of renal fibrosis was similar to wild type (WT), albeit with reduced mRNA expression of some fibrosis-related genes. In contrast, C5aR mice had significantly reduced renal fibrosis compared with WT and C5L2 mice in UUO. In vitro experiments with primary tubular cells demonstrated that deficiency for either C5aR or C5L2 led to a significantly reduced expression of tubular injury and fibrosis markers. Vice versa, stimulation of WT tubular cells with C5a significantly induced the expression of these markers, whereas the absence of either receptor abolished this induction. In conclusion, in experimental renal fibrosis C5L2 and C5aR both contribute to tubular injury, and, while C5aR acts profibrotic, C5L2 does not play a role in extracellular matrix accumulation, arguing against C5L2 functioning simply as a decoy receptor.
补体因子 C5a 有两个已知的受体，C5aR，介导促炎作用，和 C5L2，一种潜在的 C5a 诱饵受体。我们之前发现 C5a/C5aR 信号通路是肾脏中的一种强有力的促纤维化途径。在这里，我们首次测试了 C5L2 在肾脏纤维化中的作用。在单侧输尿管梗阻 (UUO) 诱导的肾脏纤维化中，C5aR 和 C5L2 的表达随着纤维化的进展而相似且逐渐增加，特别是在受损扩张的肾小管中更为明显。C5aR 或 C5L2 的遗传缺失显著减少了 UUO 诱导的肾小管损伤。然而，与 C5aR 缺陷小鼠相比，关键促炎介质的表达在 C5L2 缺陷小鼠中显著增加，但这对肾脏浸润的巨噬细胞或 T 细胞数量没有影响。此外，在 C5L2 小鼠中，细胞因子和基质金属蛋白酶抑制剂组织抑制剂 1 的表达被特异性增强。因此，尽管某些纤维化相关基因的表达减少，但 C5L2 小鼠的肾脏纤维化程度与野生型 (WT) 相似。相比之下，在 UUO 中，C5aR 小鼠的肾脏纤维化程度明显低于 WT 和 C5L2 小鼠。用原代肾小管细胞进行的体外实验表明，C5aR 或 C5L2 的缺失导致肾小管损伤和纤维化标志物的表达显著降低。相反，C5a 刺激 WT 肾小管细胞显著诱导这些标志物的表达，而缺乏任何一种受体则消除了这种诱导。总之，在实验性肾脏纤维化中，C5L2 和 C5aR 均有助于肾小管损伤，而 C5aR 起促纤维化作用，C5L2 则不在细胞外基质积聚中发挥作用，这表明 C5L2 并非简单地作为诱饵受体发挥作用。
