Gene expression analysis in a canine model of X-linked Alport syndrome
Gene expression analysis in a canine model of X-linked Alport syndrome
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DOI：
10.1007/s00335-005-0179-8
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发表时间：
2006-09-01
期刊：
影响因子：
2.5
通讯作者：
Murphy, Keith E.
中科院分区：
文献类型：
--
作者：
Greer, Kimberly A.;Higgins, Marnie A.;Murphy, Keith E.
慢性肾病（CKD）通常会因进行性间质纤维化而导致肾衰竭，并且是导致犬疾病和死亡的重要原因。疾病生物标志物和基因表达变化的鉴定将产生有关疾病进展的特定生物学途径的有价值的信息。为了实现这些目标，使用微阵列技术检查了 X 连锁 Alport 综合征 (XLAS) 犬肾皮质的基因表达变化。受影响的狗在炎症、代谢、免疫和细胞外基质生物学方面发现了广泛的变化。统计分析显示，与年龄匹配的同窝动物相比，受影响的动物中有 133 个基因被强烈诱导或抑制。许多主要组织相容性复合体 (MHC) 分子表达的改变表明免疫系统在 XLAS 中发挥着重要作用。疾病末期 COL4A1 和 TIMP-1 表达增加支持了表达增加与纤维化进展相关的建议，并证实了 COL4A1 蛋白表达增加的观察结果。簇蛋白可能是肾皮质对抗 XLAS 犬进行性损伤的主要防御之一，正如 CLU 基因表达增加所证明的那样。 SOD1、ACO1、FDXR 和 GPX1 基因表达的变化证明，在过度氧化应激期间起作用的细胞机制也可能起到阻止肾损伤的作用。这项研究使人们更好地了解间质纤维化发病机制，以及早期检测的潜在生物标志物，这些因素对于发现更有效的治疗方法至关重要，从而减少 CKD 引起的临床疾病和死亡。
Chronic kidney disease (CKD) often culminates in renal failure as a consequence of progressive interstitial fibrosis and is an important cause of illness and death in dogs. Identification of disease biomarkers and gene expression changes will yield valuable information regarding the specific biological pathways involved in disease progression. Toward these goals, gene expression changes in the renal cortex of dogs with X-linked Alport syndrome (XLAS) were examined using microarray technology. Extensive changes in inflammatory, metabolic, immune, and extracellular matrix biology were revealed in affected dogs. Statistical analysis showed 133 genes that were robustly induced or repressed in affected animals relative to age-matched littermates. Altered expression of numerous major histocompatibility complex (MHC) molecules suggests that the immune system plays a significant role in XLAS. Increased expression of COL4A1 and TIMP-1 at the end stage of disease supports the suggestion that expression increases in association with progression of fibrosis and confirms an observation of increased COL4A1 protein expression. Clusterin may function as one of the primary defenses of the renal cortex against progressive injury in dogs with XLAS, as demonstrated here by increased CLU gene expression. Cellular mechanisms that function during excess oxidative stress might also act to deter renal damage, as evidenced by alterations in gene expression of SOD1, ACO1, FDXR, and GPX1. This investigation provides a better understanding of interstitial fibrosis pathogenesis, and potential biomarkers for early detection, factors that are essential to discovering more effective treatments thereby reducing clinical illness and death due to CKD.