Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
Nat Med. 2012 Mar 11;18(4):580-8. doi: 10.1038/nm.2685.
Kidney fibrosis is a common process that leads to the progression of various types of kidney disease. We used an integrated computational and experimental systems biology approach to identify protein kinases that regulate gene expression changes in the kidneys of human immunodeficiency virus (HIV) transgenic mice (Tg26 mice), which have both tubulointerstitial fibrosis and glomerulosclerosis. We identified homeo-domain interacting protein kinase 2 (HIPK2) as a key regulator of kidney fibrosis. HIPK2 was upregulated in the kidneys of Tg26 mice and in those of patients with various kidney diseases. HIV infection increased the protein concentrations of HIPK2 by promoting oxidative stress, which inhibited the seven in absentia homolog 1 (SIAH1)-mediated proteasomal degradation of HIPK2. HIPK2 induced apoptosis and the expression of epithelial-to-mesenchymal transition markers in kidney epithelial cells by activating the p53, transforming growth factor β (TGF-β)-SMAD family member 3 (Smad3) and Wnt-Notch pathways. Knockout of HIPK2 improved renal function and attenuated proteinuria and kidney fibrosis in Tg26 mice, as well as in other murine models of kidney fibrosis. We therefore conclude that HIPK2 is a potential target for anti-fibrosis therapy.
肾脏纤维化是导致各种类型肾脏疾病进展的常见过程。我们采用综合计算和实验系统生物学方法来鉴定蛋白激酶，这些激酶调节人类免疫缺陷病毒（HIV）转基因小鼠（Tg26 小鼠）肾脏中的基因表达变化，该小鼠既有肾小管间质纤维化又有肾小球硬化。我们确定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 小鼠和各种肾脏疾病患者的肾脏中上调。HIV 感染通过促进氧化应激增加 HIPK2 的蛋白浓度，从而抑制七缺失同源物 1（SIAH1）介导的 HIPK2 蛋白酶体降解。HIPK2 通过激活 p53、转化生长因子 β（TGF-β）-SMAD 家族成员 3（Smad3）和 Wnt-Notch 通路，诱导肾脏上皮细胞凋亡和上皮间质转化标志物的表达。敲除 HIPK2 可改善 Tg26 小鼠以及其他肾脏纤维化小鼠模型的肾功能，并减轻蛋白尿和肾脏纤维化。因此，我们得出结论，HIPK2 是抗纤维化治疗的潜在靶点。
