A systems approach identifies HIPK2 as a key regulator of kidney fibrosis.
A systems approach identifies HIPK2 as a key regulator of kidney fibrosis.
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作者：
肾脏纤维化是导致肾脏疾病进展的常见过程。我们使用一种集成的计算/实验系统生物学方法来识别上游蛋白激酶，该蛋白激酶调节HIV-1转基因小鼠(TG26)肾脏中基因表达的变化，这些转基因小鼠同时患有肾小管间质纤维化和肾小球硬化。我们发现同源域相互作用蛋白激酶2(HIPK2)是肾脏纤维化的关键调节因子。HIPK2在TG26和各种肾脏疾病患者的肾脏中表达上调。HIV感染通过促进氧化应激增加HIPK2的蛋白水平，从而抑制SIAH1介导的蛋白酶体对HIPK2的降解。HIPK2通过激活P53、转化生长因子-β/Smad3和Wnt/Notch通路，诱导肾上皮细胞凋亡和上皮-间充质转分化标志物的表达。在TG26和其他肾脏纤维化动物模型中，HIPK2基因敲除改善了肾功能，减轻了蛋白尿和肾脏纤维化。我们认为，HIPK2是一种潜在的抗纤维化治疗靶点。
Kidney fibrosis is a common process that leads to the progression of kidney diseases. We used an integrated computational/experimental systems biology approach to identify upstream protein kinases that regulate gene expression changes in kidneys of HIV-1 transgenic mice (Tg26), which have both tubulo-interstitial fibrosis and glomerulosclerosis. We identified the homeo-domain interacting protein kinase 2 (HIPK2) as a key regulator of kidney fibrosis. HIPK2 was upregulated in kidneys of Tg26 and patients with various kidney diseases. HIV infection increased the protein level of HIPK2 by promoting oxidative stress, which inhibited SIAH1-mediated proteasomal degradation of HIPK2. HIPK2 induced apoptosis and expression of epithelial-mesenchymal trans-differentiation markers in kidney epithelial cells by activating p53, TGF-β/Smad3, and Wnt/Notch pathways. Knockout of HIPK2 improved renal function and attenuated proteinuria and kidney fibrosis in Tg26 as well as in other animal models of kidney fibrosis. We conclude that HIPK2 is a potential target for anti-fibrosis therapy.
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影响因子：
3
作者：
Berger SI;Posner JM;Ma'ayan A
通讯作者：
Ma'ayan A
DOI：
10.1093/bioinformatics/btp026
发表时间：
2009-03-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Lachmann A;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
19.6
作者：
Ivanovski, O;Szumilak, D;Massy, ZA
通讯作者：
Massy, ZA
影响因子：
8
作者：
Di Stefano, V;Blandino, G;D'Orazi, G
通讯作者：
D'Orazi, G
影响因子：
3.7
作者：
DICKIE, P;FELSER, J;NOTKINS, AL
通讯作者：
NOTKINS, AL