Adiponectin regulates albuminuria and podocyte function in mice
Adiponectin regulates albuminuria and podocyte function in mice
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DOI：
10.1172/jci32691
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发表时间：
2008-05-01
影响因子：
15.9
通讯作者：
Goldstein, Barry J.
中科院分区：
文献类型：
--
作者：
Sharma, Kumar;RamachandraRao, Satish;Goldstein, Barry J.
白蛋白尿增加与肥胖和糖尿病有关，是心血管和肾脏疾病的危险因素。然而，早期蛋白尿和肥胖之间的联系仍不清楚。为了确定脂联素（一种脂肪细胞衍生的激素）是否是脂肪细胞和肾脏之间的通信信号，我们在糖尿病和肾脏疾病高风险患者队列以及脂联素敲除（Ad（-/-））小鼠中进行了研究。肥胖患者的蛋白尿与血浆脂联素呈负相关，Ad（-/-）小鼠的蛋白尿增加，足细胞足突融合。在培养的足细胞中，脂联素给药与AMPK活性增加相关，脂联素和AMPK活化均降低了足细胞对白蛋白的渗透性和足细胞功能障碍，这一点可通过闭合蛋白-1易位至膜得到证实。这些作用似乎是由氧化应激的减少引起的，因为脂联素和AMPK活化都降低了足细胞中NADPH氧化酶Nox 4的蛋白水平。用脂联素治疗的Ad（-/-）小鼠表现出白蛋白尿正常化，足细胞足突消失改善，肾小球AMPK活化增加，氧化应激的尿和肾小球标志物减少。这些结果表明，脂联素是蛋白尿的关键调节因子，可能通过AMPK途径调节足细胞中的氧化应激。
Increased albuminuria is associated with obesity and diabetes and is a risk factor for cardiovascular and renal disease. However, the link between early albuminuria and adiposity remains unclear. To determine whether adiponectin, an adipocyte-derived hormone, is a communication signal between adipocytes and the kidney, we performed studies in a cohort of patients at high risk for diabetes and kidney disease as well as in adiponectin-knockout (Ad(-/-)) mice. Albuminuria had a negative correlation with plasma adiponectin in obese patients, and Ad(-/-) mice exhibited increased albuminuria and fusion of podocyte foot processes. In cultured podocytes, adiponectin administration was associated with increased activity of AMPK, and both adiponectin and AMPK activation reduced podocyte permeability to albumin and podocyte dysfunction, as evidenced by zona occludens-1 translocation to the membrane. These effects seemed to be caused by reduction of oxidative stress, as adiponectin and AMPK activation both reduced protein levels of the NADPH oxidase Nox4 in podocytes. Ad(-/-) mice treated with adiponectin exhibited normalization of albuminuria, improvement of podocyte foot process effacement, increased glomerular AMPK activation, and reduced urinary and glomerular markers of oxidant stress. These results suggest that adiponectin is a key regulator of albuminuria, likely acting through the AMPK pathway to modulate oxidant stress in podocytes.