A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy.
A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy.
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与人类 NOS3 变异相关的小鼠内皮 NOS 的适度减少会加剧糖尿病肾病。
DOI：
10.1073/pnas.1018766108
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发表时间：
2011
影响因子：
11.1
通讯作者：
Takahashi,Nobuyuki
中科院分区：
文献类型：
--
作者：
Wang,Chih-Hong;Li,Feng;Hiller,Sylvia;Kim,Hyung-Suk;Maeda,Nobuyo;Smithies,Oliver;Takahashi,Nobuyuki
人内皮型一氧化氮合酶（eNOS）基因（NOS 3）的多态性与糖尿病患者的晚期肾病和组织培养中表达降低相关。然而，缺乏NOS表达的适度遗传性降低会加重糖尿病肾病的直接证据。为了研究这种效应，我们利用了杂合129 S6/SvEvTac eNOS+/−近交雌性与携带显性秋田致糖尿病突变Ins 2 C96 Y/+的杂合C57 BL/6 J eNOS +/−近交雄性杂交的F1后代（eNOS+/+、eNOS+/−或eNOS−/−伴或不伴糖尿病）的杂种优势和遗传均一性。尽管所有C57 BL/6 J近交系eNOS−/−和eNOS+/−糖尿病小鼠在5个月前死亡，但几乎一半的F1杂交eNOS−/−和eNOS+/−糖尿病小鼠存活至7个月时死亡。与同窝出生的eNOS+/+糖尿病小鼠相比，杂合子eNOS+/−糖尿病小鼠在肾脏中表达约35%的eNOS mRNA，在肾小球中表达约25%的eNOS蛋白。这些eNOS的减少升高了血压（BP），但不升高血糖。尿白蛋白排泄、系膜扩张、肾小球硬化、系膜溶解和肾小球滤过率按以下顺序增加：eNOS+/+秋田< eNOS+/−秋田< eNOS−/−秋田，与血压无关。肾小球基底膜增厚依赖于血压升高。肾脏组织因子等炎症因子表达随肾病的加重而增加; Nos 2表达也随肾病的加重而增加。然而，令人惊讶的是，NOS表达的减少改善了糖尿病引起的氧化应激和肾小管间质纤维化的增加。我们的数据表明，与人类NOS 3变异体相关的eNOS适度降低足以增强糖尿病肾病，而不依赖于其对血压的影响。
Polymorphisms in the human endothelial nitric oxide synthase (eNOS) gene (NOS3) have been associated with advanced nephropathy in diabetic patients and with decreased expression in tissue culture. However, direct proof that modest genetic decreases ineNOSexpression worsen diabetic nephropathy is lacking. To investigate this effect, we took advantage of the hybrid vigor and genetic uniformity of the F1 progeny (eNOS+/+, eNOS+/−, or eNOS−/−with or without diabetes) of a cross between heterozygous 129S6/SvEvTac eNOS+/−inbred females and heterozygous C57BL/6J eNOS+/−inbred males carrying the dominant Akita diabetogenic mutationIns2C96Y/+. Whereas all C57BL/6J inbred eNOS−/−and eNOS+/−diabetic mice died before 5 mo, almost half of the F1 hybrid eNOS−/−and eNOS+/−diabetic mice lived until killed at 7 mo. Heterozygous eNOS+/−diabetic mice expressed ∼35%eNOSmRNA in the kidney and ∼25% glomerular eNOS protein relative to their eNOS+/+diabetic littermates. These decreases in eNOS elevated blood pressure (BP) but not blood glucose. Urinary albumin excretion, mesangial expansion, glomerulosclerosis, mesangiolysis, and glomerular filtration rate increased in the order: eNOS+/+Akita < eNOS+/−Akita < eNOS−/−Akita, independently of BP. Glomerular basement membrane thickening depended on increased BP. Renal expression of tissue factor and other inflammatory factors increased with the nephropathy;Nos2also increased. Surprisingly, however, decreasedeNOSexpression ameliorated the increases in oxidative stress and tubulointerstitial fibrosis caused by diabetes. Our data demonstrate that a modest decrease in eNOS, comparable to that associated with humanNOS3variants, is sufficient to enhance diabetic nephropathy independently of its effects on BP.