Hakroush Samy, Cebulla Angelika, Schaldecker Thomas, Behr Daniel, Mundel Peter, Weins Astrid
Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and.
Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
J Am Soc Nephrol. 2014 May;25(5):927-38. doi: 10.1681/ASN.2013070687. Epub 2013 Dec 12.
Damage to podocytes is a central pathomechanism of proteinuric kidney disease. However, it is not fully understood how podocyte injury evolves to progressive glomerulopathies such as FSGS or collapsing glomerulopathy. In particular, the role of parietal epithelial cells remains controversial. Here, we show that adriamycin induces DNA damage and podocyte lysis in mice without evidence of autophagy, endoplasmic reticulum stress, or necroptosis. After extensive podocyte loss, activated parietal cells mediated tuft re-epithelialization by two distinct mechanisms. In the majority of glomeruli, vacuolized parietal epithelial cells attached to denuded glomerular basement membrane and, occasionally, disengaged from the parietal basement membrane. Less frequently, parietal epithelial cells covered the denuded visceral basement membrane via formation of proliferative pseudocrescents. Notably, "visceralized" parietal epithelial cells did not express vascular endothelial growth factor but upregulated hypoxia-inducible factor 1 expression. The presence of visceralized parietal epithelial cells in sclerosing and collapsing lesions in a kidney biopsy from a patient with diabetes underscores the human relevance of our findings. In conclusion, repopulation of the glomerular tuft by parietal cells may represent a compensatory response to extensive podocyte loss. Our results suggest, however, that visceralized parietal epithelial cells cannot induce revascularization of the hyalinized tuft, resulting in hypoxic cell death and irreversible destruction of the glomerulus.
足细胞损伤是蛋白尿性肾病的核心发病机制。然而,目前尚不完全清楚足细胞损伤如何演变为诸如局灶节段性肾小球硬化(FSGS)或塌陷性肾小球病等进行性肾小球疾病。特别是,壁层上皮细胞的作用仍存在争议。在此,我们表明阿霉素可诱导小鼠DNA损伤和足细胞溶解,且无自噬、内质网应激或坏死性凋亡的证据。在大量足细胞丢失后,活化的壁层细胞通过两种不同机制介导肾小球毛细血管丛的再上皮化。在大多数肾小球中,空泡化的壁层上皮细胞附着于裸露的肾小球基底膜,偶尔也会从壁层基底膜脱离。较少见的是,壁层上皮细胞通过形成增殖性假新月体覆盖裸露的脏层基底膜。值得注意的是,“脏层化”的壁层上皮细胞不表达血管内皮生长因子,但上调缺氧诱导因子1的表达。在一名糖尿病患者的肾活检标本中,硬化和塌陷性病变中存在脏层化的壁层上皮细胞,这突出了我们研究结果与人类情况的相关性。总之,壁层细胞对肾小球毛细血管丛的再填充可能代表了对大量足细胞丢失的一种代偿反应。然而,我们的结果表明,脏层化的壁层上皮细胞不能诱导玻璃样变的毛细血管丛再血管化,从而导致缺氧性细胞死亡和肾小球的不可逆破坏。