Exacerbation of albuminuria and renal fibrosis in subtotal renal ablation model of adiponectin-knockout mice
Exacerbation of albuminuria and renal fibrosis in subtotal renal ablation model of adiponectin-knockout mice
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DOI：
10.1161/atvbaha.107.147645
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发表时间：
2007-09-01
影响因子：
8.7
通讯作者：
Funahashi, Tohru
中科院分区：
文献类型：
--
作者：
Ohashi, Koji;Iwatani, Hirotsugu;Funahashi, Tohru
目的-肥胖日益被认为是肾脏疾病的主要危险因素。我们以前报道过肥胖患者的血浆脂联素水平降低，而且脂联素对2型糖尿病和高血压有防御作用。在这项研究中，我们研究了脂联素在肾脏疾病中的作用。方法和结果-脂联素基因敲除小鼠(APN-KO)和野生型(WT)小鼠进行了肾大部切除(5/6)。这一过程导致脂联素在残肾肾小球和间质中显著积聚。与WT小鼠相比，APN-KO小鼠的尿白蛋白排泄、肾小球肥大和肾小管间质纤维化明显加重。KO组肾小球内巨噬细胞浸润及血管细胞黏附分子(VCAM)-1、单核细胞趋化蛋白-1(MCP-1)、肿瘤坏死因子(TNF)-α、转化生长因子(TGF)-β1、I型/III型胶原和NADPH氧化酶组分的mRNA水平显著高于WT组。腺病毒介导的脂联素治疗APN-KO小鼠后，可改善蛋白尿、肾小球肥大和肾小管间质纤维化，降低VCAM-1、MCP-1、肿瘤坏死因子-α、转化生长因子-β1、I型/III型胶原和NADPH氧化酶组分mRNAs的水平，使其水平降至与WT小鼠相同水平。结论：脂联素可通过调节炎症和氧化应激而积聚到受损小鼠肾脏，预防肾小球和肾小管间质损伤。
Objective - Obesity is recognized increasingly as a major risk factor for kidney disease. We reported previously that plasma adiponectin levels were decreased in obesity, and that adiponectin had defensive properties against type 2 diabetes and hypertension. In this study, we investigated the role of adiponectin for kidney disease in a subtotal nephrectomized mouse model.Methods and Results - Subtotal (5/6) nephrectomy was performed in adiponectin-knockout (APN-KO) and wild-type (WT) mice. The procedure resulted in significant accumulation of adiponectin in glomeruli and interstitium in the remnant kidney. Urinary albumin excretion, glomerular hypertrophy, and tubulointerstitial fibrosis were significantly worse in APN-KO mice compared with WT mice. Intraglomerular macrophage infiltration and mRNA levels of vascular cell adhesion molecule (VCAM)-1, MCP-1, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta 1, collagen type I/III, and NADPH oxidase components were significantly increased in KO mice compared with WT mice. Treatment of APN-KO mice with adenovirus-mediated adiponectin resulted in amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis and reduced the elevated levels of VCAM-1, MCP-1, TNF-alpha, TGF-beta 1, collagen type I/III, and NADPH oxidase components mRNAs to the same levels as those in WT mice.Conclusions - Adiponectin accumulates to the injured kidney, and prevents glomerular and tubulointerstitial injury through modulating inflammation and oxidative stress.