Intravenous administration of hepatocyte growth factor gene ameliorates diabetic nephropathy in mice
Intravenous administration of hepatocyte growth factor gene ameliorates diabetic nephropathy in mice
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DOI：
10.1097/01.asn.0000139479.09658.ee
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发表时间：
2004-10-01
影响因子：
13.6
通讯作者：
Liu, YH
中科院分区：
文献类型：
--
作者：
Dai, CS;Yang, JW;Liu, YH
糖尿病肾病的特征在于肾功能的进行性丧失、持续性蛋白尿和细胞外基质的无情积累，导致肾小球硬化和间质纤维化。本研究探讨了外源性肝细胞生长因子（HGF）长期表达对正常和糖尿病肾脏的潜在影响。通过裸质粒载体静脉注射人HGF基因导致大量HGF蛋白特异性定位于肾小球，尽管在肾脏中的转基因mRNA水平极低。在用链脲佐菌素造成糖尿病的单侧肾切除小鼠中，外源性HGF基因的递送改善了糖尿病肾病的进展。肝细胞生长因子减少糖尿病小鼠尿白蛋白和总蛋白排泄。外源性肝细胞生长因子也减轻肾小球系膜扩张，减少纤维连接蛋白和I型胶原沉积，并防止间质肌成纤维细胞活化。此外，HGF可防止肾小球和肾小管中的肾细胞凋亡。此外，HGF的表达抑制肾TGF-β 1的表达，并降低尿TGF-β 1蛋白水平。因此，尽管HGF对糖尿病肾病的作用存在争议，但这些观察结果表明，补充HGF有益于改善小鼠的糖尿病肾功能不全。
Diabetic nephropathy is characterized by progressive loss of renal function, persistent proteinuria, and relentless accumulation of extracellular matrix leading to glomerulosclerosis and interstitial fibrosis. This study investigated the potential effects of long-term expression of exogenous hepatocyte growth factor (HGF) on normal and diabetic kidneys. Intravenous injection of human HGF gene via naked plasmid vector resulted in abundant HGF protein specifically localized in renal glomeruli, despite an extremely low level of transgene mRNA in the kidney. In uninephrectomized mice made diabetic with streptozotocin, delivery of exogenous HGF gene ameliorated the progression of diabetic nephropathy. HGF attenuated urine albumin and total protein excretion in diabetic mice. Exogenous HGF also mitigated glomerular mesangial expansion, reduced fibronectin and type I collagen deposition, and prevented interstitial myofibroblast activation. In addition, HGF prevented kidney cells from apoptotic death in the glomeruli and tubulointerstitium. Moreover, expression of HGF inhibited renal expression of TGF-beta1 and reduced urine level of TGF-beta1 protein. Therefore, despite the effects of HGF on diabetic nephropathy being controversial, these observations suggest that supplementation of HGF is beneficial in ameliorating diabetic renal insufficiency in mice.