Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy
Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy
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DOI：
10.1016/j.ajpath.2011.02.039
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发表时间：
2011-06-01
影响因子：
6
通讯作者：
Murphy-Ullrich, Joanne E.
中科院分区：
文献类型：
--
作者：
Lu, Ailing;Miao, Mi;Murphy-Ullrich, Joanne E.
转化生长因子-β（TGF-β）是糖尿病肾病发病机制中的关键。血小板反应蛋白1（TSP 1）的表达在糖尿病中增加，TSP 1在体外和糖尿病动物模型中调节潜在的TGF-β活化。在此，我们研究了阻断TSP 1依赖性TGF-β活化对1型糖尿病小鼠模型（C57 BL/6 J-Ins 2（秋田））肾脏疾病进展的影响，作为糖尿病肾病的靶向治疗。接受单侧肾切除术的秋田和对照C57 BL/6小鼠接受15周每周三次的Lp。用3或30 mg/kg LSKL肽、对照SLLK肽或盐水处理。在2型糖尿病小鼠（db/db）中评估全身性LSKL肽对皮肤伤口愈合的作用。在用30 mg/kg LSKL肽处理的秋田小鼠中，蛋白尿（尿白蛋白水平和白蛋白/肌酸酐比率）显著改善。LSIU治疗降低了尿TGF-β活性和肾脏磷酸化Smad 2/3水平，并改善了肾小管间质损伤（纤连蛋白）和足细胞（nephrin）的标志物。然而，LSKL并没有改变肾小球硬化或肾小球结构。LSKL不增加肿瘤发生率或炎症或损害糖尿病伤口愈合。这些数据表明，通过阻断TSP 1依赖性TGF-β活化选择性靶向过度的TGF-β活性代表了一种治疗糖尿病肾病的治疗策略，其保留了TGF-β的稳态功能。(Am病理学杂志2011，178：2573-2584。DOI：10.1016/j.ajpath.2011.02.039）
Transforming growth factor-beta (TGF-beta) is key in the pathogenesis of diabetic nephropathy. Thrombospondin 1 (TSP1) expression is increased in diabetes, and TSP1 regulates latent TGF-beta activation in vitro and in diabetic animal models. Herein, we investigate the effect of blockade of TSP1-dependent TGF-beta 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 Lp. 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. LSIU, treatment reduced urinary TGF-beta activity and renal phospho-Smad2/3 levels and unproved 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-beta activity through blockade of TSP1-dependent TGF-beta activation represents a therapeutic strategy for treating diabetic nephropathy that preserves the homeostatic functions of TGF-beta. (Am J Pathol 2011, 178:2573-2584. DOI: 10.1016/j.ajpath.2011.02.039)