肾 Dnase1 酶活性和蛋白表达在鼠和人膜性增殖性狼疮肾炎中被选择性关闭。
Renal Dnase1 enzyme activity and protein expression is selectively shut down in murine and human membranoproliferative lupus nephritis.
机构信息
Department of Biochemistry, Institute of Medical Biology, Medical Faculty, University of Tromsø, Tromsø, Norway.
出版信息
PLoS One. 2010 Aug 10;5(8):e12096. doi: 10.1371/journal.pone.0012096.
BACKGROUND
Deposition of chromatin-IgG complexes within glomerular membranes is a key event in the pathogenesis of lupus nephritis. We recently reported an acquired loss of renal Dnase1 expression linked to transformation from mild to severe membranoproliferative lupus nephritis in (NZBxNZW)F1 mice. As this may represent a basic mechanism in the progression of lupus nephritis, several aspects of Dnase1 expression in lupus nephritis were analyzed.
METHODOLOGY/PRINCIPAL FINDINGS: Total nuclease activity and Dnase1 expression and activity was evaluated using in situ and in vitro analyses of kidneys and sera from (NZBxNZW)F1 mice of different ages, and from age-matched healthy controls. Immunofluorescence staining for Dnase1 was performed on kidney biopsies from (NZBxNZW)F1 mice as well as from human SLE patients and controls. Reduced serum Dnase1 activity was observed in both mesangial and end-stage lupus nephritis. A selective reduction in renal Dnase1 activity was seen in mice with massive deposition of chromatin-containing immune complexes in glomerular capillary walls. Mice with mild mesangial nephritis showed normal renal Dnase1 activity. Similar differences were seen when comparing human kidneys with severe and mild lupus nephritis. Dnase1 was diffusely expressed within the kidney in normal and mildly affected kidneys, whereas upon progression towards end-stage renal disease, Dnase1 was down-regulated in all renal compartments. This demonstrates that the changes associated with development of severe nephritis in the murine model are also relevant to human lupus nephritis.
CONCLUSIONS/SIGNIFICANCE: Reduction in renal Dnase1 expression and activity is limited to mice and SLE patients with signs of membranoproliferative nephritis, and may be a critical event in the development of severe forms of lupus nephritis. Reduced Dnase1 activity reflects loss in the expression of the protein and not inhibition of enzyme activity.
背景
染色质-IgG 复合物在肾小球膜中的沉积是狼疮性肾炎发病机制中的一个关键事件。我们最近报道了一种获得性的肾 Dnase1 表达缺失，与（NZBxNZW）F1 小鼠从轻度到严重的膜性增殖性狼疮肾炎的转化有关。由于这可能代表狼疮性肾炎进展的基本机制，因此分析了狼疮性肾炎中 Dnase1 表达的几个方面。
方法/主要发现：使用原位和体外分析，评估了来自不同年龄的（NZBxNZW）F1 小鼠以及年龄匹配的健康对照的肾脏和血清中的总核酸酶活性和 Dnase1 表达和活性。对（NZBxNZW）F1 小鼠的肾脏活检标本以及人类 SLE 患者和对照进行了 Dnase1 的免疫荧光染色。在患有大量染色质免疫复合物沉积于肾小球毛细血管壁的系膜和终末期狼疮肾炎患者中观察到血清 Dnase1 活性降低。在伴有大量染色质免疫复合物沉积于肾小球毛细血管壁的小鼠中，肾 Dnase1 活性出现选择性降低。在患有轻度系膜肾炎的小鼠中，肾 Dnase1 活性正常。当比较严重和轻度狼疮肾炎的人类肾脏时，也观察到了类似的差异。在正常和轻度受累的肾脏中，Dnase1 在肾脏内弥漫表达，而在向终末期肾脏病进展时，Dnase1 在所有肾脏区室中下调。这表明与小鼠模型中严重肾炎发展相关的变化也与人类狼疮肾炎相关。
结论/意义：肾 Dnase1 表达和活性的降低仅限于具有膜增殖性肾炎迹象的小鼠和 SLE 患者，并且可能是严重形式狼疮性肾炎发展的关键事件。Dnase1 活性降低反映了蛋白质表达的丧失，而不是酶活性的抑制。
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