Department of Cell Systems and Anatomy, University of Texas Health, San Antonio, Texas, USA.
Department of Pathology, University of Texas Health, San Antonio, Texas, USA.
FASEB J. 2019 Jan;33(1):373-387. doi: 10.1096/fj.201800555RR. Epub 2018 Jul 5.
Chronic exposure of tubular renal cells to high glucose contributes to tubulointerstitial changes in diabetic nephropathy. In the present study, we identified a new fibrosis gene called galectin-1 (Gal-1), which is highly expressed in tubular cells of kidneys of type 1 and type 2 diabetic mouse models. Gal-1 protein and mRNA expression showed significant increase in kidney cortex of heterozygous Akita and db/db mice compared with wild-type mice. Mouse proximal tubular cells exposed to high glucose showed significant increase in phosphorylation of Akt and Gal-1. We cloned Gal-1 promoter and identified the transcription factor AP4 as binding to the Gal-1 promoter to up-regulate its function. Transfection of cells with plasmid carrying mutations in the binding sites of AP4 to Gal-1 promoter resulted in decreased protein function of Gal-1. In addition, inhibition of Gal-1 by OTX-008 showed significant decrease in p-Akt/AP4 and protein-promoter activity of Gal-1 and fibronectin. Moreover, down-regulation of AP4 by small interfering RNA resulted in a significant decrease in protein expression and promoter activity of Gal-1. We found that kidney of Gal-1 mice express very low levels of fibronectin protein. In summary, Gal-1 is highly expressed in kidneys of type 1 and 2 diabetic mice, and AP4 is a major transcription factor that activates Gal-1 under hyperglycemia. Inhibition of Gal-1 by OTX-008 blocks activation of Akt and prevents accumulation of Gal-1, suggesting a novel role of Gal-1 inhibitor as a possible therapeutic target to treat renal fibrosis in diabetes.-Al-Obaidi, N., Mohan, S., Liang, S., Zhao, Z., Nayak, B. K., Li, B., Sriramarao, P., Habib, S. L. Galectin-1 is a new fibrosis protein in type 1 and type 2 diabetes.
慢性暴露于高葡萄糖会导致肾小管细胞发生变化，从而导致糖尿病肾病的肾小管间质变化。在本研究中，我们鉴定了一种新的纤维化基因，称为半乳糖凝集素-1（Gal-1），其在 1 型和 2 型糖尿病小鼠模型的肾小管细胞中高度表达。与野生型小鼠相比，杂合子 Akita 和 db/db 小鼠的肾脏皮质中 Gal-1 蛋白和 mRNA 表达显著增加。高糖暴露的小鼠近端肾小管细胞中 Akt 和 Gal-1 的磷酸化显著增加。我们克隆了 Gal-1 启动子，并鉴定出转录因子 AP4 与 Gal-1 启动子结合以上调其功能。用携带 AP4 与 Gal-1 启动子结合位点突变的质粒转染细胞，导致 Gal-1 的蛋白功能降低。此外，OTX-008 抑制 Gal-1 可显著降低 p-Akt/AP4 和 Gal-1 和纤维连接蛋白的蛋白启动子活性。此外，用小干扰 RNA 下调 AP4 可导致 Gal-1 的蛋白表达和启动子活性显著降低。我们发现 Gal-1 小鼠的肾脏表达的纤维连接蛋白蛋白水平非常低。总之，Gal-1 在 1 型和 2 型糖尿病小鼠的肾脏中高度表达，AP4 是高血糖下激活 Gal-1 的主要转录因子。OTX-008 抑制 Gal-1 可阻断 Akt 的激活并防止 Gal-1 的积累，这表明 Gal-1 抑制剂作为治疗糖尿病肾病纤维化的潜在治疗靶点具有新的作用。-Al-Obaidi，N.，Mohan，S.，Liang，S.，Zhao，Z.，Nayak，B.K.，Li，B.，Sriramarao，P.，Habib，S.L. Galectin-1 是 1 型和 2 型糖尿病的新型纤维化蛋白。
