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Shiga Toxin Promotes Podocyte Injury in Experimental Hemolytic Uremic Syndrome via Activation of the Alternative Pathway of Complement
发布于：2014年3月3日 文字：【大】【中】【小】
J Am Soc Nephrol. 2014 Feb 27. [Epub ahead of print]
Shiga Toxin Promotes Podocyte Injury in Experimental Hemolytic Uremic Syndrome via Activation of the Alternative Pathway of Complement.
Locatelli M1, Buelli S, Pezzotta A, Corna D, Perico L, Tomasoni S, Rottoli D, Rizzo P, Conti D, Thurman JM, Remuzzi G, Zoja C, Morigi M.
Abstract
Shiga toxin (Stx)-producing Escherichia coli is the offending agent of postdiarrhea-associated hemolytic uremic syndrome (HUS), a disorder of glomerular ischemic damage and widespread microvascular thrombosis. We previously documented that Stx induces glomerular complementactivation, generating C3aresponsible for microvascular thrombosis in experimental HUS. Here, we show that the presence of C3 deposits on podocytes is associated with podocyte damage and loss in HUS mice generated by the coinjection of Stx2 and LPS. Because podocyte adhesion to the glomerular basement membrane is mediated by integrins, the relevance of integrin-linked kinase (ILK) signals in podocyte dysfunction was evaluated.Podocyte expression of ILK increased after the injection of Stx2/LPS and preceded the upregulation of Snail and downregulation of nephrin and α-actinin-4.Factor B deficiency or pretreatment with an inhibitory antibody to factor B protected mice against Stx2/LPS-induced podocytedysregulation.
Similarly, pretreatment with a C3areceptor antagonist limited podocyte loss and changes in ILK, Snail, and α-actinin-4 expression.
In cultured podocytes, treatment with C3areduced α-actinin-4 expression and promoted ILK-dependent nuclear expression of Snail and cell motility. These results suggest that Stx-induced activation of the alternative pathway of complement and generation of C3apromotes ILK signaling, leading to podocyte dysfunction and loss in Stx-HUS.
KEYWORDS:
acute renal failure, complement, hemolytic uremic syndrome, podocyte
志贺毒素在HUS模型中通过激活补体旁路途经促进内皮细胞损伤
产志贺毒素(Stx)的大肠杆菌可导致腹泻相关型溶血尿毒综合征（HUS）-- 一种可导致肾小球缺血损伤和全身微血管血栓的疾病。我们之前报道了Stx可导致肾小球局部补体激活、产生C3a，C3a可进一步在HUS模型中导致微血管血栓形成。本研究展示了HUS小鼠模型中，用Stx2与LPS共刺激时，足细胞上C3沉积与足细胞损伤和脱落相关。足细胞依靠整合素粘附在肾小球基底膜上，故进一步研究整合素连接激酶(ILK)信号转导以反映足细胞功能失调。Stx2/LPS注射后，足细胞ILK表达升高，且其升高早于Snail 的上调和nephrin及α-actinin-4的下调。B因子基因敲出或抗B因子阻断抗体均可在Stx2/LPS注射引发的足细胞功能失调模型中起保护作用。类似的是， C3a受体拮抗剂的预注射可以减轻足细胞脱落及ILK, Snail, 和α-actinin-4 表达的改变。在体外培养的足细胞中，C3a预刺激可以下调α-actinin-4 的表达及上调ILK依赖的Snail的核表达及细胞迁移。这些结果提示Stx引发的补体旁路途经活化及C3a的产生可促进ILK的信号转导，导致足细胞功能失调及脱落。