Effect of hereditary obesity on renal expressions of NO synthase, caveolin-1, AKt, guanylate cyclase, and calmodulin
Effect of hereditary obesity on renal expressions of NO synthase, caveolin-1, AKt, guanylate cyclase, and calmodulin
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DOI：
10.1111/j.1523-1755.2005.00747.x
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发表时间：
2005-12-01
影响因子：
19.6
通讯作者：
Vaziri, ND
中科院分区：
文献类型：
--
作者：
Li, Z;Rodríguez-Iturbe, B;Vaziri, ND
背景。肥胖已成为世界范围内糖尿病、心血管疾病和肾功能不全的主要原因。肥胖的Zucker大鼠表现为贪食、肥胖、胰岛素抵抗、高脂血症和肾小球硬化，经常被用作研究代谢综合征遗传形式的模型。一氧化氮在肾脏功能和结构的保存中起着重要作用。本研究旨在验证该模型中肾脏疾病可能与肾脏内皮（eNOS）和神经NO合成酶（nNOS）下调相关的假设。本研究进一步探讨了调控NOS组成亚型活性的caveolin-1、phospho AKt和calmodulin的表达，以及参与NO信号传导的可溶性鸟苷酸环化酶（sGC）的表达。研究了22周龄雄性肥胖和瘦弱的Zucker大鼠。测定小鼠体重、血脂、尿白蛋白排泄量及肾组织中上述蛋白的丰度。与瘦Zucker大鼠相比，肥胖大鼠的血清葡萄糖和动脉压不变，而尿NO代谢产物（NO chi）排泄和肾组织硝基酪氨酸丰度显著降低（表明NO产生受到抑制）。伴有明显的肾小球硬化、小管间质损伤、肾免疫细胞浸润，肾组织eNOS和nNOS明显下调，小窝蛋白-1轻度降低，钙调蛋白、磷酸化akt和sgc不变。遗传性肥胖可导致肾eNOS和nNOS下调，NO生成显著减少，在糖尿病和高血压发病前发生肾小球硬化。
Background. Obesity has emerged as a major cause of diabetes, cardiovascular disease, and renal insufficiency worldwide. Obese Zucker rats exhibit hyperphagia, obesity, insulin resistance, hyperlipidemia, and glomerulosclerosis and are frequently used as a model to study hereditary form of metabolic syndrome. Nitric oxide plays a major role in preservation of renal function and structure. The present study was designed to test the hypothesis that renal disease in this model may be associated with down-regulation of endothelial (eNOS) and neuromal NO synthases (nNOS) in the kidney. The study further sought to explore expressions of caveolin-1, phospho AKt, and calmodulin, which regulate activities of constituitive NOS isoforms, as well as soluble guanylate cyclase (sGC), which is involved in NO signaling.Methods. Twenty-two-week-old male obese and lean Zucker rats were studied. Body weight, serum lipids, urine albumin excretion, and renal tissue abundance of the above proteins were determined.Results. Serum glucose and arterial pressure were unchanged, whereas urinary NO metabolite (NO chi) excretion and renal tissue nitrotyrosine abundance were markedly reduced (denoting depressed NO production) in the obese versus lean Zucker rats. This was accompanied by significant glomerulosclerosis, tubulointerstitial damage, renal immune cell infiltration, marked down-regulations of renal tissue eNOS and nNOS, mild reduction of caveolin-1, and unchanged calmodulin, phospho-AKt, and sGC.Conclusion. Hereditary obesity can result in down-regulations of kidney eNOS and nNOS, marked reduction of NO production, and glomerulosclerosis prior to the onset of frank diabetes and hypertension.