Role of smooth muscle protein SM22α in glomerular epithelial cell injury
Role of smooth muscle protein SM22α in glomerular epithelial cell injury
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DOI：
10.1152/ajprenal.00187.2010
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发表时间：
2011-04-01
影响因子：
4.2
通讯作者：
Shankland, Stuart J.
中科院分区：
文献类型：
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作者：
Marshall, Caroline B.;Krofft, Ron D.;Shankland, Stuart J.
Marshall CB、Krofft RD、Blonski MJ、Kowalewska J、Logar CM、Pippin JW、Kim F、Feil R、Alpers CE、Shankland SJ。平滑肌蛋白SM22α在肾小球上皮细胞损伤中的作用。 Am J Physiol Renal Physiol 300：F1026-F1042，2011。首次发表于 2011 年 2 月 2 日； doi:10.1152/ajprenal.00187.2010.-足细胞在正常条件下被认为是成熟肾脏中的终末分化细胞。面对损伤，足细胞可能沿着几种可能的途径进行，包括去分化和增殖、持续的细胞周期停滞、肥大、凋亡或坏死。越来越多的证据表明，转分化为失调的表型也可能是一种潜在的细胞命运。我们之前曾报道过，SM22 α（一种肌动蛋白结合蛋白，被认为是平滑肌分化的最早标志物之一）的转录物在被动海曼肾炎 (PHN) 大鼠的肾小球中上调近 70 倍。相反，正常成年大鼠肾小球中不存在 SM22 α 转录本。本研究的目的是确定 SM22 α 在肾脏发育过程中的表达及其在以足细胞损伤和蛋白尿为特征的肾小球疾病中的作用。在肾小球发生和足细胞分化期间，SM22α在肾小球中表达。这种表达随着肾小球的成熟而消失。除了在 mRNA 和蛋白质水平上证实的 PHN 中的 SM22 α 诱导外，SM22 α 也在多种蛋白尿疾病中被诱导，包括实验动物模型（嘌呤霉素氨基核苷肾病、阿霉素肾病、被动性肾毒性肾炎和饮食诱导的肥胖）和人类疾病（塌陷性肾小球病、糖尿病肾病、经典局灶节段性肾小球硬化、IgA 肾病、微小病变病、膜性肾病和膜增生性肾小球肾炎）。通过腹腔注射羊抗兔肾小球抗体 12.5 mg/20 g 体重 x 2 剂量（n = 12-15/组）在 SM22 α +/+ 和 SM22 α -/- 小鼠中诱导新月体肾小球肾炎，并在第 7 天和 14 天时对小鼠实施安乐死。与SM22 α -/- 小鼠相比，SM22 α +/+ 小鼠的组织病理学参数表现出更严重的疾病。此外，患病 SM22 α +/+ 小鼠的细胞凋亡（裂解的 caspase-3 免疫染色）较多，足细胞较少（Wilms 肿瘤-1 免疫染色），增殖较少（Ki-67 免疫染色）。此外，患病 SM22 α +/+ 小鼠中 Erk1/2 的激活降低。我们得出的结论是，肾小球上皮细胞中 SM22 α 的从头表达影响新月体肾小球肾炎的病程。
Marshall CB, Krofft RD, Blonski MJ, Kowalewska J, Logar CM, Pippin JW, Kim F, Feil R, Alpers CE, Shankland SJ. Role of smooth muscle protein SM22 alpha in glomerular epithelial cell injury. Am J Physiol Renal Physiol 300: F1026-F1042, 2011. First published February 2, 2011; doi:10.1152/ajprenal.00187.2010.-Podocytes are considered terminally differentiated cells in the mature kidney under normal conditions. In the face of injury, podocytes may proceed along several possible pathways, including dedifferentiation and proliferation, persistent cell cycle arrest, hypertrophy, apoptosis, or necrosis. There is mounting evidence that transdifferentiation into a dysregulated phenotype may also be a potential cell fate. We have previously reported that the transcript of SM22 alpha, an actin-binding protein considered one of the earliest markers of smooth muscle differentiation, is upregulated nearly 70-fold in glomeruli of rats with passive Heymann nephritis (PHN). In contrast, the SM22 alpha transcript is absent in normal adult rat glomeruli. The purpose of this study was to define SM22 alpha's expression during kidney development and its role in glomerular diseases characterized by podocyte injury and proteinuria. During glomerulogenesis and podocyte differentiation, SM22 alpha was expressed in glomeruli. This expression disappeared with glomerular maturation. Along with SM22 alpha induction in PHN, confirmed at both mRNA and protein levels, SM22 alpha was also induced across a broad range of proteinuric diseases, including experimental animal models (puromycin aminonucleoside nephropathy, adriamycin nephropathy, passive nephrotoxic nephritis, and diet-induced obesity) and human diseases (collapsing glomerulopathy, diabetic nephropathy, classic focal segmental glomerulosclerosis, IgA nephropathy, minimal-change disease, membranous nephropathy, and membranoproliferative glomerulonephritis). Crescentic glomerulonephritis was induced in SM22 alpha +/+ and SM22 alpha -/- mice by intraperitoneal injection of sheep anti-rabbit glomeruli antibody 12.5 mg/20 g body wt x 2 doses (n = 12-15/group), with mice euthanized at 7 and 14 days. Compared with SM22 alpha -/- mice, SM22 alpha +/+ mice demonstrated worse disease by histopathological parameters. In addition, there was greater apoptosis (cleaved caspase-3 immunostaining), fewer podocytes (Wilms' tumor-1 immunostaining), and less proliferation (Ki-67 immunostaining) in diseased SM22 alpha +/+ mice. Furthermore, there was decreased activation of Erk1/2 in diseased SM22 alpha +/+ mice. We conclude that the de novo expression of SM22 alpha in glomerular epithelial cells affects the course of crescentic glomerulonephritis.