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FOXA1 Suppresses SATB1 Transcription and Inactivates the Wnt/β-Catenin Pathway to Alleviate Diabetic Nephropathy in a Mouse Model
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy ( IF 2.8 ) Pub Date : 2021-09-10 , DOI: 10.2147/dmso.s314709 Hong Zhu 1 , Jiarui Peng 1 , Wei Li 1
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy ( IF 2.8 ) Pub Date : 2021-09-10 , DOI: 10.2147/dmso.s314709 Hong Zhu 1 , Jiarui Peng 1 , Wei Li 1
Affiliation
Objective: Diabetic nephropathy (DN) represents the most common diabetic complication that may lead to end-stage renal disease. This work focused on the effect of FOXA1 on the DN development and the molecular mechanism.
Methods: A mouse model of DN was induced by high-fat diets and streptozotocin. The concentrations of blood glucose and urinary protein in mice, and the pathological changes in mouse kidney tissues were determined. A podocyte cell line MPC-5 was treated with high glucose (HG) to mimic a DN-like condition in vitro. FOXA1 and SATB1 were overexpressed in HG-treated MPC-5 cells and in DN mice to explore their effects on cell proliferation and apoptosis, and on pathological changes in mouse kidney tissues. The binding relationship between FOXA1 and STAB1 was predicted and validated. Activation of the Wnt/β-catenin pathway was detected.
Results: FOXA1 was poorly expressed in the kidney tissues of DN mice. Overexpression of FOXA1 reduced the concentrations of fasting blood glucose and 24-h urinary protein in mice. It also suppressed the accumulation of glomerular mesangial matrix and hyperplasia of glomerular basement membrane, and reduced collagen deposition and interstitial fibrosis in mouse kidney. Also, FOXA1 reduced HG-induced apoptosis of MPC-5 cells. FOXA1 bound to the promoter region of SATB1 for transcription suppression. Overexpression of SATB1 activated the Wnt/β-catenin pathway and blocked the protective roles of FOXA1 in DN mice and in HG-treated MPC-5 cells.
Conclusion: This study demonstrated that FOXA1 transcriptionally suppresses SATB1 expression and inactivates the Wnt/β-catenin signaling pathway, thereby inhibiting podocyte apoptosis and DN progression.
Keywords: diabetic nephropathy, FOXA1, SATB1, Wnt/β-catenin, MPC-5
中文翻译：
FOXA1 在小鼠模型中抑制 SATB1 转录并灭活 Wnt/β-连环蛋白通路以减轻糖尿病肾病
目的：糖尿病肾病（DN）是最常见的糖尿病并发症，可能导致终末期肾病。这项工作的重点是 FOXA1 对 DN 发展的影响和分子机制。
方法：DN 小鼠模型由高脂饮食和链脲佐菌素诱导。测定小鼠血糖、尿蛋白浓度及小鼠肾组织病理变化。用高葡萄糖 (HG) 处理足细胞系 MPC-5 以在体外模拟 DN 样条件。FOXA1 和 SATB1 在 HG 处理的 MPC-5 细胞和 DN 小鼠中过表达，以探索它们对细胞增殖和凋亡以及对小鼠肾组织病理变化的影响。预测并验证了 FOXA1 和 STAB1 之间的结合关系。检测到 Wnt/β-连环蛋白途径的激活。
结果：FOXA1 在 DN 小鼠的肾组织中表达不佳。FOXA1 的过表达降低了小鼠空腹血糖和 24 小时尿蛋白的浓度。它还抑制了肾小球系膜基质的积累和肾小球基底膜的增生，减少了小鼠肾脏的胶原沉积和间质纤维化。此外，FOXA1 减少了 HG 诱导的 MPC-5 细胞凋亡。FOXA1 与 SATB1 的启动子区域结合以抑制转录。SATB1 的过表达激活了 Wnt/β-catenin 通路并阻断了 FOXA1 在 DN 小鼠和 HG 处理的 MPC-5 细胞中的保护作用。
结论：该研究表明，FOXA1 转录抑制 SATB1 表达并使 Wnt/β-catenin 信号通路失活，从而抑制足细胞凋亡和 DN 进展。
关键词：糖尿病肾病，FOXA1，SATB1，Wnt/β-catenin，MPC-5
更新日期：2021-09-09
Methods: A mouse model of DN was induced by high-fat diets and streptozotocin. The concentrations of blood glucose and urinary protein in mice, and the pathological changes in mouse kidney tissues were determined. A podocyte cell line MPC-5 was treated with high glucose (HG) to mimic a DN-like condition in vitro. FOXA1 and SATB1 were overexpressed in HG-treated MPC-5 cells and in DN mice to explore their effects on cell proliferation and apoptosis, and on pathological changes in mouse kidney tissues. The binding relationship between FOXA1 and STAB1 was predicted and validated. Activation of the Wnt/β-catenin pathway was detected.
Results: FOXA1 was poorly expressed in the kidney tissues of DN mice. Overexpression of FOXA1 reduced the concentrations of fasting blood glucose and 24-h urinary protein in mice. It also suppressed the accumulation of glomerular mesangial matrix and hyperplasia of glomerular basement membrane, and reduced collagen deposition and interstitial fibrosis in mouse kidney. Also, FOXA1 reduced HG-induced apoptosis of MPC-5 cells. FOXA1 bound to the promoter region of SATB1 for transcription suppression. Overexpression of SATB1 activated the Wnt/β-catenin pathway and blocked the protective roles of FOXA1 in DN mice and in HG-treated MPC-5 cells.
Conclusion: This study demonstrated that FOXA1 transcriptionally suppresses SATB1 expression and inactivates the Wnt/β-catenin signaling pathway, thereby inhibiting podocyte apoptosis and DN progression.
Keywords: diabetic nephropathy, FOXA1, SATB1, Wnt/β-catenin, MPC-5
中文翻译：
FOXA1 在小鼠模型中抑制 SATB1 转录并灭活 Wnt/β-连环蛋白通路以减轻糖尿病肾病
目的：糖尿病肾病（DN）是最常见的糖尿病并发症，可能导致终末期肾病。这项工作的重点是 FOXA1 对 DN 发展的影响和分子机制。
方法：DN 小鼠模型由高脂饮食和链脲佐菌素诱导。测定小鼠血糖、尿蛋白浓度及小鼠肾组织病理变化。用高葡萄糖 (HG) 处理足细胞系 MPC-5 以在体外模拟 DN 样条件。FOXA1 和 SATB1 在 HG 处理的 MPC-5 细胞和 DN 小鼠中过表达，以探索它们对细胞增殖和凋亡以及对小鼠肾组织病理变化的影响。预测并验证了 FOXA1 和 STAB1 之间的结合关系。检测到 Wnt/β-连环蛋白途径的激活。
结果：FOXA1 在 DN 小鼠的肾组织中表达不佳。FOXA1 的过表达降低了小鼠空腹血糖和 24 小时尿蛋白的浓度。它还抑制了肾小球系膜基质的积累和肾小球基底膜的增生，减少了小鼠肾脏的胶原沉积和间质纤维化。此外，FOXA1 减少了 HG 诱导的 MPC-5 细胞凋亡。FOXA1 与 SATB1 的启动子区域结合以抑制转录。SATB1 的过表达激活了 Wnt/β-catenin 通路并阻断了 FOXA1 在 DN 小鼠和 HG 处理的 MPC-5 细胞中的保护作用。
结论：该研究表明，FOXA1 转录抑制 SATB1 表达并使 Wnt/β-catenin 信号通路失活，从而抑制足细胞凋亡和 DN 进展。
关键词：糖尿病肾病，FOXA1，SATB1，Wnt/β-catenin，MPC-5
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