Role of Nox4 in murine models of kidney disease
Role of Nox4 in murine models of kidney disease
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DOI：
10.1016/j.freeradbiomed.2012.06.027
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发表时间：
2012-08-15
影响因子：
7.4
通讯作者：
Brandes, Ralf P.
中科院分区：
文献类型：
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作者：
Babelova, Andrea;Avaniadi, Despina;Brandes, Ralf P.
Nox 4是一种在肾脏中高度表达的产生过氧化氢的NADPH氧化酶，其与培养细胞中的上皮细胞损伤和糖尿病诱导的细胞功能障碍有关。然而，该酶在体内肾脏病理学中的作用尚不清楚。为了解决这个问题，三个实验动物模型的肾损伤（链脲佐菌素糖尿病I。单侧输尿管结扎（UUO）和5/6肾切除术（5/6 Nx））。Nox 4贡献了超过80%的二苯碘鎓敏感的H2 O2形成的新鲜分离的肾小管通过Amplex红测定。在链脲佐菌素糖尿病中，由他莫昔芬激活的cre重组酶引起的Nox 4急性缺失增加了白蛋白尿，而WT和Nox 4 *（/）* 小鼠之间的基质沉积相似。有趣的是，肾脏Nox 4的表达，主要定位于肾小管细胞，在糖尿病的过程中减少，这是不相关的Nox 1或Nox 2的代偿性上调。在UUO模型中，Nox 4 *（/）* 小鼠肾脏中ICAM I、结缔组织生长因子和纤连蛋白的表达高于对照小鼠。同样在该模型中，Nox 4水平在疾病过程中下降。在SV 129和SV 129-Nox 4（-/-）小鼠中进行的5/6 Nx模型中，在高血压和蛋白尿的发展方面没有发现品系之间的差异。总的来说，肾脏的第一个体内数据不支持Nox 4是肾脏疾病的主要驱动因素的观点。相反，在特定条件下，Nox 4甚至可以轻微限制损伤和疾病进展。(C)2012 Elsevier Inc. All rights reserved.
Nox4 is a hydrogen peroxide-producing NADPH oxidase highly expressed in the kidney which has been linked to epithelial cell injury and diabetic-induced cellular dysfunction in cultured cells. The role of the enzyme for renal pathology in vivo, however, is unclear. To address this, three experimental animal models of renal injury (streptozotocin diabetes I. unilateral ureteral ligation (UUO), and 5/6 nephrectomy (5/6Nx)) were studied in either Nox4-inducible (Nox4*(/)*) or constitutive knockout (Nox4(-/-)) mice. Nox4 contributed more than 80% of diphenylene iodonium-sensitive H2O2 formation of freshly isolated tubules determined by Amplex Red assay. In streptozotocin diabetes, acute deletion of Nox4 by tamoxifen-activated cre-recombinase increased albuminuria, whereas matrix deposition was similar between WT and Nox4*(/)* mice. Interestingly, renal Nox4 expression, mainly localized to tubular cells, decreased in the course of diabetes and this was not associated with a compensatory upregulation of Nox1 or Nox2. In the UUO model, renal expression of ICAM I, connective tissue growth factor, and fibronectin were higher in kidneys of Nox4*(/)* than control mice. Also in this model, levels of Nox4 decreased in the course of the disease. In the 5/6Nx model, which was performed in SV129 and SV129-Nox4(-/-) mice, no difference in the development of hypertension and albuminuria was found between the strains. Collectively, the first in vivo data of the kidney do not support the view that Nox4 is a main driver of renal disease. It rather appears that under specific conditions Nox4 may even slightly limit injury and disease progression. (C) 2012 Elsevier Inc. All rights reserved.