Gaarkeuken Hilde, Siezenga Machiel A, Zuidwijk Kim, van Kooten Cees, Rabelink Ton J, Daha Mohamed R, Berger Stefan P
Department of Nephrology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Am J Physiol Renal Physiol. 2008 Nov;295(5):F1397-403. doi: 10.1152/ajprenal.90313.2008. Epub 2008 Aug 27.
Activation of filtered complement products on the brush border of the tubular epithelium is thought to be a key factor underlying proteinuria-induced tubulointerstitial injury. However, the mechanism of tubular complement activation is still unclear. Recent studies on mechanisms of complement activation indicate a key role for properdin in the initiation of an alternative pathway. We hypothesized that properdin serves as a focal point for complement activation on the tubulus. We observed a strong staining for properdin on the luminal surface of the tubules in kidney biopsies from patients with proteinuric renal disease. In vitro experiments revealed dose-dependent binding of properdin to proximal tubular epithelial cells (PTEC), whereas no significant binding to endothelial cells was detected. Exposure of PTEC with normal human serum as a source of complement resulted in complement activation with deposition of C3 and generation of C5b-9. These effects were virtually absent with properdin-deficient serum. Preincubation of PTEC with properdin before addition of properdin-depleted serum fully restored complement activation on the cells, strongly suggesting a key role for properdin in the activation of complement at the tubular surface. In proteinuric renal disease, filtered properdin may bind to PTEC and act as a focal point for alternative pathway activation. We propose that this contribution of properdin is pivotal in tubular complement activation and subsequent damage. Interference with properdin binding to tubular cells may provide an option for the treatment of proteinuric renal disease.
滤过的补体产物在肾小管上皮细胞刷状缘的激活被认为是蛋白尿诱导的肾小管间质损伤的关键因素。然而，肾小管补体激活的机制仍不清楚。最近关于补体激活机制的研究表明，备解素在替代途径的启动中起关键作用。我们假设备解素是肾小管补体激活的焦点。我们观察到，在蛋白尿性肾病患者的肾活检组织中，肾小管腔表面有强烈的备解素染色。体外实验显示，备解素与近端肾小管上皮细胞（PTEC）呈剂量依赖性结合，而未检测到与内皮细胞的明显结合。用正常人血清作为补体来源处理PTEC，导致补体激活，伴有C3沉积和C5b-9生成。而在缺乏备解素的血清中，这些效应几乎不存在。在添加缺乏备解素的血清之前，先用备解素预孵育PTEC，可完全恢复细胞上的补体激活，这强烈表明备解素在肾小管表面补体激活中起关键作用。在蛋白尿性肾病中，滤过的备解素可能与PTEC结合，并作为替代途径激活的焦点。我们认为，备解素的这种作用在肾小管补体激活及随后的损伤中起关键作用。干扰备解素与肾小管细胞的结合可能为蛋白尿性肾病的治疗提供一种选择。
