Decay-Accelerating Factor Restrains Complement Activation and Delays Progression of Murine cBSA-Induced Membranous Nephropathy.
Decay-Accelerating Factor Restrains Complement Activation and Delays Progression of Murine cBSA-Induced Membranous Nephropathy.
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DOI：
10.34067/kid.0000000000000122
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发表时间：
2023-06-01
期刊：
影响因子：
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通讯作者：
Cravedi P
中科院分区：
文献类型：
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作者：
Budge KL;Verlato A;Bin S;Salem FE;Perin L;La Manna G;Zaza G;Fiaccadori E;Cantarelli C;Cravedi P
在阳离子牛血清白蛋白（cBSA）诱导的膜性肾病（MN）小鼠模型中，补体调节因子衰变加速因子上调并抑制补体激活。使用C3 aR的遗传缺失或药理学拮抗作用的研究表明，cBSA诱导的MN中补体激活的主要效应机制是C3 a/C3 aR信号传导。C3 a形成和/或C3 aR介导的信号传导代表了MN的假设驱动疗法的有希望的靶点。补体激活被认为在膜性肾病（MN）中起主要的致病作用，但其效应机制仍不清楚。甚至更少的研究是足细胞表达的补体调节剂，包括衰变加速因子（decay-accelerating factor，简称decF）在疾病病理生理学中的作用。我们通过在WT、C3 aR −/−和C3 aR −/− BALB/c小鼠中连续注射阳离子牛血清白蛋白（cBSA）诱导MN，并测量疾病的严重程度（通过白蛋白尿、BUN、血清白蛋白和肾小球组织学变化）和肾小球中补体激活的迹象（C1 q、C3 b和膜攻击复合物的免疫荧光）。我们还用选择性C3 aR拮抗剂处理了cBSA诱导的MN的小鼠，并测量了相同的读数。cBSA诱导的MN与肾小球表达增加相关。与野生型动物相比，基因缺失导致补体激活增加和疾病严重程度升高。用C3 aR拮抗剂治疗cBSA注射的C3 aR −/−小鼠可降低疾病严重程度。同样，C3 aR −/−动物受到保护，免受cBSA诱导的MN，尽管IgG沉积在肾小球和补体激活。这些小鼠肾小球中C1 q和C3 b沉积的证据表明，肾小球中IgG-cBSA免疫复合物的形成通过经典途径激活补体。在cBSA诱导的损伤中，足细胞上调抑制补体激活的β 1受体表达。然而，在长时间损伤后，补体激活克服了免疫调节作用，导致可溶性过敏毒素C3 a的形成，通过C3 aR信号传导，促进肾小球损伤和cBSA诱导的MN疾病进展。考虑到越来越多的补体靶向治疗，我们的研究结果可能对MN患者的治疗产生重大的转化作用。
In a murine model of cationic bovine serum albumin (cBSA)–induced membranous nephropathy (MN), complement regulator decay-accelerating factor is upregulated and restrains complement activation. Studies using genetic deletion or pharmacological antagonism of C3aR indicate that the main effector mechanism of complement activation in cBSA-induced MN is C3a/C3aR signaling. C3a formation and/or C3aR-mediated signaling represent promising targets for hypothesis-driven therapies for MN. Complement activation is believed to play a major pathogenic role in membranous nephropathy (MN), but its effector mechanisms are still unclear. Even less investigated is the role of podocyte-expressed complement regulators, including decay-accelerating factor (DAF) in disease pathophysiology. We induced MN by serial injections of cationic bovine serum albumin (cBSA) in WT, DAF−/−, and C3aR−/− BALB/c mice and measured disease severity (by albuminuria, BUN, serum albumin, and glomerular histologic changes) and signs of complement activation in the glomeruli (immunofluorescence for C1q, C3b, and membrane attack complex). We also treated DAF−/− mice with cBSA-induced MN with a selective C3aR antagonist and measured the same readouts. cBSA-induced MN was associated with increased glomerular expression of DAF. Genetic deletion of DAF resulted in increased complement activation and higher disease severity than in WT animals. Treating cBSA-injected DAF−/− mice with a C3aR antagonist reduced disease severity. Similarly, C3aR−/− animals were protected from cBSA-induced MN, despite IgG deposition in the glomeruli and complement activation. Evidence of C1q and C3b deposition in the glomeruli of these mice suggest that IgG-cBSA immune complex formation in the glomeruli activates complement through the classical pathway. On cBSA-induced injury, podocytes upregulate DAF expression, which restrains complement activation. However, after prolonged injury, complement activation overcomes DAF regulatory effects leading to the formation of soluble anaphylatoxin C3a that, by signaling through C3aR, promotes glomerular injury and cBSA-induced MN disease progression. Considering the growing number of complement targeting therapies, our findings may have major translational effect on the treatment of patients with MN.