Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis.
Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis.
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DOI：
10.1371/journal.pone.0066164
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Olaharski AJ
中科院分区：
文献类型：
--
作者：
Ness D;Ren Z;Gardai S;Sharpnack D;Johnson VJ;Brennan RJ;Brigham EF;Olaharski AJ
遗传学证据将LRRK 2基因突变与帕金森病风险增加联系起来，目前还没有神经保护或神经恢复疗法。虽然LRRK 2在正常细胞功能中的作用尚未完全描述，但有证据表明与免疫和肾脏功能有关。LRRK 2缺陷型和野生型大鼠的比较研究调查了该基因对这些大鼠表型的影响。在LRRK 2缺失大鼠中观察到显著的体重增加，并且伴随着胰岛素和胰岛素样生长因子的显著增加。此外，LRRK 2缺陷大鼠在所有评估动物的肾小管上皮细胞中均表现出肾脏形态学和组织病理学变化。肾形态学的这些扰动伴随着基因敲除动物的尿液和血浆中脂质运载蛋白-2的显著降低。通过免疫表型鉴定了LRRK 2敲除和野生型动物之间脾脏细胞组成的显著变化，并且与对大鼠适应性流感病毒（RAIV）和肺炎链球菌双重感染的反应的细微差异相关。LRRK 2跨代谢和肾脏过程和病理类别的本体通路分析表明，硫氧还蛋白网络可能在扰乱这些器官系统中发挥作用。LRRK 2缺失大鼠的表型表明影响代谢、免疫功能和肾脏稳态的复杂生物学。这些数据需要扩展，以更好地了解激酶结构域的作用或基因的其他生物学功能，以更好地为药理学抑制剂的开发提供信息。
Genetic evidence links mutations in the LRRK2 gene with an increased risk of Parkinson’s disease, for which no neuroprotective or neurorestorative therapies currently exist. While the role of LRRK2 in normal cellular function has yet to be fully described, evidence suggests involvement with immune and kidney functions. A comparative study of LRRK2-deficient and wild type rats investigated the influence that this gene has on the phenotype of these rats. Significant weight gain in the LRRK2 null rats was observed and was accompanied by significant increases in insulin and insulin-like growth factors. Additionally, LRRK2-deficient rats displayed kidney morphological and histopathological alterations in the renal tubule epithelial cells of all animals assessed. These perturbations in renal morphology were accompanied by significant decreases of lipocalin-2, in both the urine and plasma of knockout animals. Significant alterations in the cellular composition of the spleen between LRRK2 knockout and wild type animals were identified by immunophenotyping and were associated with subtle differences in response to dual infection with rat-adapted influenza virus (RAIV) and Streptococcus pneumoniae. Ontological pathway analysis of LRRK2 across metabolic and kidney processes and pathological categories suggested that the thioredoxin network may play a role in perturbing these organ systems. The phenotype of the LRRK2 null rat is suggestive of a complex biology influencing metabolism, immune function and kidney homeostasis. These data need to be extended to better understand the role of the kinase domain or other biological functions of the gene to better inform the development of pharmacological inhibitors.
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影响因子：
--
作者：
Gaig, C;Ezquerra, M;Tolosa, E
通讯作者：
Tolosa, E
影响因子：
9.3
作者：
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通讯作者：
Bubacco L
影响因子：
3.7
作者：
Kim B;Yang MS;Choi D;Kim JH;Kim HS;Seol W;Choi S;Jou I;Kim EY;Joe EH
通讯作者：
Joe EH
影响因子：
5.8
作者：
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通讯作者：
Elbein, Steven C.
影响因子：
3.5
作者：
Dodson, Mark W.;Zhang, Ting;Guo, Ming
通讯作者：
Guo, Ming