大量研究报道了C反应蛋白(CRP)和补体激活在糖尿病肾病(DKD)中的致病作用。然而,考虑到CRP对补体激活的有效调节作用,目前尚不清楚CRP是否通过调节补体激活参与DKD的发病机制.此外,这项工作的重点是大鼠的补体激活,旨在解决大鼠CRP能否激活补体系统的争议。为了解决这个问题,补体效应子C3a,C5a,和C5b-9在患有糖尿病肾病(DN)的人类患者中进行了检查,Crp-/-,和患有STZ糖尿病DKD的huCRPtg大鼠。与wt和huCRPtg大鼠相比,Crp-/-大鼠在血液和肾小球中显示出更多的C3a积累。在DKD大鼠中评估自噬和凋亡之间的平衡,与wt和huCRPtg大鼠相比,Crp-/-大鼠的足细胞自噬增加。同时,建立了稳定的CRP过表达和CRP敲除细胞系,并用于证明CRP在高糖条件下抑制C3a诱导的足细胞自噬。我们进一步证实,CRP对C3a诱导的足细胞自噬的抑制依赖于C3aR的表达,并且这种作用可以用C3aR拮抗剂和激动剂逆转。因此,我们的研究结果提供了证据,表明CRP通过抑制C3a/C3aR轴信号传导抑制足细胞自噬加速DKD的发展,这可能有助于开发一种新的治疗策略来管理足细胞自噬和DKD。此外,已证明大鼠CRP在自体补体和种间补体的激活方面与人类CRP相同。
Numerous studies have reported the pathogenic roles of C-reactive protein (CRP) and complement activation in diabetic kidney disease (DKD) individually. However, considering the potent regulatory effect of CRP on complement activation, it remains unclear whether CRP participates in DKD pathogenesis by regulating complement activation. Moreover, this work focuses on complement activation in rats, which aims at settling the dispute that whether rat CRP can activate the complement system. To address this question, the complement effectors C3a, C5a, and C5b-9 were examined in human patients with diabetic nephropathy (DN) and wt, Crp-/- , and huCRPtg rats with STZ-diabetic DKD. The Crp-/- rats showed more C3a accumulation in blood and glomeruli than wt and huCRPtg rats. The balance between autophagy and apoptosis was evaluated in DKD rats, and Crp-/- rats showed increased podocyte autophagy compared with wt and huCRPtg rats. Meanwhile, stable CRP-overexpression and CRP-knockout cell lines were established and used to demonstrate that CRP suppresses C3a-induced podocyte autophagy under high-glucose conditions. We further verified that the inhibition of C3a-induced podocyte autophagy by CRP was dependent on C3aR expression and that this effect could be reversed with a C3aR antagonist and agonist. Therefore, our findings provide evidence that CRP suppresses podocyte autophagy to accelerate the development of DKD by inhibiting C3a/C3aR axis signaling, which may help in the development of a new therapeutic strategy for the management of podocyte autophagy and DKD. In addition, rat CRP has been shown to be identical to human CRP in the activation of autologous complement and interspecific complement.