Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Am J Pathol. 2011 Jun;178(6):2573-86. doi: 10.1016/j.ajpath.2011.02.039.
Transforming growth factor-β (TGF-β) is key in the pathogenesis of diabetic nephropathy. Thrombospondin 1 (TSP1) expression is increased in diabetes, and TSP1 regulates latent TGF-β activation in vitro and in diabetic animal models. Herein, we investigate the effect of blockade of TSP1-dependent TGF-β activation on progression of renal disease in a mouse model of type 1 diabetes (C57BL/6J-Ins2(Akita)) as a targeted treatment for diabetic nephropathy. Akita and control C57BL/6 mice who underwent uninephrectomy received 15 weeks of thrice-weekly i.p. treatment with 3 or 30 mg/kg LSKL peptide, control SLLK peptide, or saline. The effects of systemic LSKL peptide on dermal wound healing was assessed in type 2 diabetic mice (db/db). Proteinuria (urinary albumin level and albumin/creatinine ratio) was significantly improved in Akita mice treated with 30 mg/kg LSKL peptide. LSKL treatment reduced urinary TGF-β activity and renal phospho-Smad2/3 levels and improved markers of tubulointerstitial injury (fibronectin) and podocytes (nephrin). However, LSKL did not alter glomerulosclerosis or glomerular structure. LSKL did not increase tumor incidence or inflammation or impair diabetic wound healing. These data suggest that selective targeting of excessive TGF-β activity through blockade of TSP1-dependent TGF-β activation represents a therapeutic strategy for treating diabetic nephropathy that preserves the homeostatic functions of TGF-β.
转化生长因子-β（TGF-β）在糖尿病肾病的发病机制中起关键作用。糖尿病中血栓反应蛋白 1（TSP1）的表达增加，TSP1 调节体外和糖尿病动物模型中潜伏 TGF-β的激活。在此，我们研究了阻断 TSP1 依赖性 TGF-β激活对 1 型糖尿病（C57BL/6J-Ins2（Akita））小鼠模型中肾脏疾病进展的影响，作为糖尿病肾病的靶向治疗。Akita 和对照 C57BL/6 小鼠接受单侧肾切除术，并接受为期 15 周的每周 3 次腹腔内注射 3 或 30mg/kg LSKL 肽、对照 SLLK 肽或生理盐水治疗。在 2 型糖尿病小鼠（db/db）中评估了全身 LSKL 肽对皮肤伤口愈合的影响。用 30mg/kg LSKL 肽治疗的 Akita 小鼠的蛋白尿（尿白蛋白水平和白蛋白/肌酐比值）显著改善。LSKL 治疗降低了尿 TGF-β活性和肾磷酸化 Smad2/3 水平，并改善了肾小管间质损伤标志物（纤连蛋白）和足细胞（nephrin）。然而，LSKL 并未改变肾小球硬化或肾小球结构。LSKL 没有增加肿瘤发生率或炎症，也没有损害糖尿病伤口愈合。这些数据表明，通过阻断 TSP1 依赖性 TGF-β激活来选择性靶向过度的 TGF-β活性，代表了一种治疗糖尿病肾病的治疗策略，可保留 TGF-β的稳态功能。
