Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autonoma (UAM), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Madrid, Spain.
Division of Nephrology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
BMJ Open Diabetes Res Care. 2020 Sep;8(1). doi: 10.1136/bmjdrc-2020-001242.
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease worldwide. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway participates in the development and progression of DN. Among the different mechanisms involved in JAK/STAT negative regulation, the family of suppressor of cytokine signaling (SOCS) proteins has been proposed as a new target for DN. Our aim was to evaluate the effect of SOCS1 mimetic peptide in a mouse model of obesity and type 2 diabetes (T2D) with progressive DN.
Six-week-old BTBR (black and tan brachyuric) mice with the ob/ob (obese/obese) leptin-deficiency mutation were treated for 7 weeks with two different doses of active SOCS1 peptide (MiS1 2 and 4 µg/g body weight), using inactive mutant peptide (Mut 4 µg) and vehicle as control groups. At the end of the study, the animals were sacrificed to obtain blood, urine and kidney tissue for further analysis.
Treatment of diabetic mice with active peptide significantly decreased urine albumin to creatinine ratio by up to 50%, reduced renal weight, glomerular and tubulointerstitial damage, and restored podocyte numbers. Kidneys from treated mice exhibited lower inflammatory infiltrate, proinflammatory gene expression and STAT activation. Concomitantly, active peptide administration modulated redox balance markers and reduced lipid peroxidation and cholesterol transporter gene expression in diabetic kidneys.
Targeting SOCS proteins by mimetic peptides to control JAK/STAT signaling pathway ameliorates albuminuria, morphological renal lesions, inflammation, oxidative stress and lipotoxicity, and could be a therapeutic approach to T2D kidney disease.
糖尿病肾病（DN）是全球慢性肾脏病的主要病因。Janus 激酶/信号转导和转录激活因子（JAK/STAT）途径参与了 DN 的发生和进展。在 JAK/STAT 负调控的不同机制中，细胞因子信号转导抑制因子（SOCS）蛋白家族已被提议作为 DN 的新靶点。我们的目的是评估 SOCS1 模拟肽在肥胖和 2 型糖尿病（T2D）合并进行性 DN 的肥胖 BTBR（黑棕褐色短毛肥胖）ob/ob（瘦素缺陷）小鼠模型中的作用。
6 周龄 BTBR 小鼠具有 ob/ob（肥胖/肥胖）瘦素缺乏突变，用两种不同剂量的活性 SOCS1 肽（MiS1 2 和 4 µg/g 体重）治疗 7 周，用非活性突变肽（Mut 4 µg）和载体作为对照组。在研究结束时，处死动物以获得血液、尿液和肾脏组织进行进一步分析。
用活性肽治疗糖尿病小鼠可使尿白蛋白与肌酐比值降低高达 50%，减少肾脏重量、肾小球和肾小管间质损伤，并恢复足细胞数量。治疗小鼠的肾脏表现出较低的炎症浸润、促炎基因表达和 STAT 激活。同时，活性肽给药调节氧化还原平衡标志物，并降低糖尿病肾脏中的脂质过氧化和胆固醇转运基因表达。
通过模拟肽靶向 SOCS 蛋白来控制 JAK/STAT 信号通路可改善白蛋白尿、肾脏形态学病变、炎症、氧化应激和脂毒性，可能成为 T2D 肾病的一种治疗方法。
