自身免疫相关肾脏疾病(ARKD),包括微小病变肾病(MCN),膜性肾病(MN),IgA肾病(IgAN),和狼疮性肾炎(LN),显著影响肾功能。这些疾病的特征是局部免疫复合物的形成和随后补体系统的激活,导致肾脏损伤和蛋白尿。尽管已知肾小球损伤的模式,导致跨ARKD肾小管损伤的特定分子机制仍未得到充分研究.使用激光捕获显微切割和液相色谱-串联质谱(LC-MS/MS)对福尔马林固定的石蜡包埋样品的肾小管组织进行比较蛋白质组学分析。该队列由10名正常对照(NC)组成,5MCN,4MN,17Igan,21名LN患者。临床参数和组织病理学评估与蛋白质组学发现相结合,以全面调查潜在的致病过程。临床评估表明肾小球有明显损伤,ARKD患者尿蛋白水平升高和血浆白蛋白水平降低反映了这一点。组织学分析证实了不同程度的肾小管损伤和免疫复合物的沉积。蛋白质组学分析发现蛋白质表达的显著变化,特别是在补体成分(C3,C4A,C4B,C8G,CFB,和SERPINA1)和线粒体蛋白(ATP5F1E和ATP5PD),强调跨ARKD的补体系统和线粒体蛋白的常见变化。这些改变表明了一种新的补体-线粒体-上皮-间质转化(EMT)途径轴,该轴有助于ARKD中的肾小管损伤。值得注意的是,发现肾小管ARKD患者的CFB发生显着变化,暗示它是一个治疗靶点。这项研究强调了补体激活和线粒体功能障碍在ARKD发病机制中的重要性。并提出CFB作为抑制补体激活和减轻肾小管损伤的潜在治疗靶点。未来的研究应验证补体-线粒体-EMT通路轴,并探讨CFB抑制剂在缓解ARKD进展中的作用和机制。
Autoimmune related kidney diseases (ARKDs), including minimal change nephropathy (MCN), membranous nephropathy (MN), IgA nephropathy (IgAN), and lupus nephritis (LN), significantly affect renal function. These diseases are characterized by the formation of local immune complexes and the subsequent activation of the complement system, leading to kidney damage and proteinuria. Despite the known patterns of glomerular injury, the specific molecular mechanisms that contribute to renal tubular damage across ARKDs remain underexplored. Laser capture microdissection and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to conduct a comparative proteomic analysis of renal tubular tissues from formalin-fixed paraffin-embedded samples. The cohort comprised of 10 normal controls (NC), 5 MCN, 4 MN, 17 IgAN, and 21 LN patients. Clinical parameters and histopathological assessments were integrated with proteomic findings to comprehensively investigate underlying pathogenic processes. Clinical evaluation indicated significant glomerular damage, as reflected by elevated urinary protein levels and reduced plasma albumin levels in patients with ARKD. Histological analyses confirmed varying degrees of tubular damage and deposition of immune complexes. Proteomic analyses identified significant changes in protein expression, particularly in complement components (C3, C4A, C4B, C8G, CFB, and SERPINA1) and mitochondrial proteins (ATP5F1E and ATP5PD), highlighting the common alterations in the complement system and mitochondrial proteins across ARKDs. These alterations suggest a novel complement-mitochondrial-epithelial-mesenchymal transition (EMT) pathway axis that contributes to tubular damage in ARKDs. Notably, significant alterations in CFB in tubular ARKD patients were revealed, implicating it as a therapeutic target. This study underscores the importance of complement activation and mitochondrial dysfunction in the pathogenesis of ARKDs, and proposes CFB as a potential therapeutic target to inhibit complement activation and mitigate tubular damage. Future research should validate the complement-mitochondrial-EMT pathway axis and explore the effects and mechanisms of CFB inhibitors in alleviating ARKD progression.