Molecular Basis of Renal Adaptation in a Murine Model of Congenital Obstructive Nephropathy
Molecular Basis of Renal Adaptation in a Murine Model of Congenital Obstructive Nephropathy
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DOI：
10.1371/journal.pone.0072762
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发表时间：
2013-09-04
期刊：
影响因子：
3.7
通讯作者：
McHugh, Kirk M.
中科院分区：
文献类型：
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作者：
Becknell, Brian;Carpenter, Ashley R.;McHugh, Kirk M.
先天性梗阻性肾病是慢性肾脏疾病的常见原因，也是儿童肾移植的主要指征。先天性梗阻时肾脏的细胞和分子反应尚不完全清楚。在这项研究中，我们评估了在megabladder（mgb（-/-））小鼠中分级肾积水的肾脏中的整体转录，以更好地理解先天性梗阻性肾病的病理生理学。在mgb（-/-）肾中诱导了与肾重塑/修复相关的三条主要途径，与肾积水程度无关。这些途径包括类维生素A信号传导、类固醇激素代谢和肾脏对损伤的反应。在mgb（-/-）肾中，尿路上皮增生和在肾尿路上皮完整性和维持中起作用的基因表达选择性增加。Ngal/Lcn 2是急性肾损伤的标志物，在36%的肾积水程度较高的肾脏中升高。Ngal（高）与Ngal（低）肾脏的评价确定了几种新的肾损伤候选标志物的表达。这项研究表明，在mgb（-/-）小鼠中进行性肾积水的发展导致肾适应，包括肾尿路上皮的形态和潜在功能的显着变化。这些观察结果将允许开发新的生物标志物和治疗方法来治疗先天性梗阻背景下的进行性肾损伤。
Congenital obstructive nephropathy is a common cause of chronic kidney disease and a leading indication for renal transplant in children. The cellular and molecular responses of the kidney to congenital obstruction are incompletely characterized. In this study, we evaluated global transcription in kidneys with graded hydronephrosis in the megabladder (mgb(-/-)) mouse to better understand the pathophysiology of congenital obstructive nephropathy. Three primary pathways associated with kidney remodeling/repair were induced in mgb(-/-) kidneys independent of the degree of hydronephrosis. These pathways included retinoid signaling, steroid hormone metabolism, and renal response to injury. Urothelial proliferation and the expression of genes with roles in the integrity and maintenance of the renal urothelium were selectively increased in mgb(-/-) kidneys. Ngal/Lcn2, a marker of acute kidney injury, was elevated in 36% of kidneys with higher grades of hydronephrosis. Evaluation of Ngal(high) versus Ngal(low) kidneys identified the expression of several novel candidate markers of renal injury. This study indicates that the development of progressive hydronephrosis in mgb(-/-) mice results in renal adaptation that includes significant changes in the morphology and potential functionality of the renal urothelium. These observations will permit the development of novel biomarkers and therapeutic approaches to progressive renal injury in the context of congenital obstruction.