Molecular and Cellular Mechanisms for Proteinuria in Minimal Change Disease
Molecular and Cellular Mechanisms for Proteinuria in Minimal Change Disease
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DOI：
10.3389/fmed.2018.00170
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发表时间：
2018-06-11
影响因子：
3.9
通讯作者：
Ghiggeri, G. M.
中科院分区：
文献类型：
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作者：
Bertelli, Roberta;Bonanni, Alice;Ghiggeri, G. M.
微小病变病（MCD）是一种临床疾病，其特征是急性肾病综合征，组织学检查无明显肾脏病变，对类固醇反应良好。然而，该疾病的频繁复发需要与类固醇相关的额外治疗。这种多药依赖和频繁复发可能导致疾病随时间演变为局灶节段性肾小球硬化（FSGS）。这两种疾病之间的差异还没有很好的定义，因为这两种疾病的分子机制可能是相同的。在某些情况下，遗传分析可以区分MCD和FSGS;然而，也有重叠的情况。已经提出了关于MCD的潜在机制和潜在分子触发器的几种假设。大多数研究是在部分模拟MCD的蛋白尿动物模型上进行的，可能有助于研究肾小球硬化演变;然而，它们并未证明MCD和FSGS之间存在明确的分离。嘌呤霉素氨基糖苷和阿霉素肾病是肾小球氧化损伤的模型，其特征为在发病时类似MCD的肾小球基底膜聚阴离子丢失，以及在更晚期阶段类似FSGS的肾小球硬化。此外，布法罗/Mna大鼠存在MCD的初始病变，随后演变为FSGS;由于该大鼠品系继承了过表达Th 2细胞因子的独特特征，因此这种肾损伤机制更加明确。在脂多糖肾病（一种与B7-1（CD 80）相关的肾毒性免疫学疾病）中，小鼠出现持续数天的一过性蛋白尿。总的来说，动物模型是有用的和必要的，考虑到它们再现了从MCD到FSGS的演变，这部分是由于蛋白尿的持续性。T/Treg/B细胞在人MCD中的作用已被讨论。许多细胞因子、免疫调节机制和一些分子已被定义为蛋白尿的特异性病因。然而，单细胞亚群或分子作为MCD原因的假设并没有得到研究的支持，相互作用的过程似乎更符合逻辑。氧化剂、Th 2型细胞因子、Th 17、TGFAP、B7-1（CD 80）、CD 40/CD 40 L、c-Mip、TNF、uPA/suPAR、Angiopoietin-like 4等的相互作用或相互影响仍有待明确证实。全基因组测序研究可以帮助确定特定的遗传特征，证明MCD的定义是一个“临床-病理-遗传实体”。"
Minimal Change Disease (MCD) is a clinical condition characterized by acute nephrotic syndrome, no evident renal lesions at histology and good response to steroids. However, frequent recurrence of the disease requires additional therapies associated with steroids. Suchmulti-drug dependence and frequent relapses may cause disease evolution to focal and segmental glomerulosclerosis (FSGS) over time. The differences between the two conditions are not well defined, since molecular mechanisms may be shared by the two diseases. In some cases, genetic analysis can make it possible to distinguish MCD from FSGS; however, there are cases of overlap. Several hypotheses on mechanisms underlying MCD and potential molecular triggers have been proposed. Most studies were conducted on animal models of proteinuria that partially mimic MCD and may be useful to study glomerulosclerosis evolution; however, they do not demonstrate a clear-cut separation between MCD and FSGS. Puromycin Aminonucleoside and Adriamycin nephrosis are models of glomerular oxidative damage, characterized by loss of glomerular basement membrane polyanions resembling MCD at the onset and, at more advanced stages, by glomerulosclerosis resembling FSGS. Also Buffalo/Mna rats present initial lesions of MCD, subsequently evolving to FSGS; this mechanism of renal damage is clearer since this rat strain inherits the unique characteristic of overexpressing Th2 cytokines. In Lipopolysaccharide nephropathy, an immunological condition of renal toxicity linked to B7-1(CD80), mice develop transient proteinuria that lasts a few days. Overall, animal models are useful and necessary considering that they reproduce the evolution from MCD to FSGS that is, in part, due to persistence of proteinuria. The role of T/Treg/Bcells on human MCD has been discussed. Many cytokines, immunomodulatory mechanisms, and several molecules have been defined as a specific cause of proteinuria. However, the hypothesis of a single cell subset or molecule as cause of MCD is not supported by research and an interactive process seems more logical. The implication or interactive role of oxidants, Th2 cytokines, Th17, Tregs, B7-1(CD80), CD40/CD40L, c-Mip, TNF, uPA/suPAR, Angiopoietin-like 4 still awaits a definitive confirmation. Whole genome sequencing studies could help to define specific genetic features that justify a definition of MCD as a "clinical-pathology-genetic entity."