Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice
Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice
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DOI：
10.1681/asn.2006070798
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发表时间：
2006-10-01
影响因子：
13.6
通讯作者：
Harris, Raymond C.
中科院分区：
文献类型：
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作者：
Zhao, Hui John;Wang, Suwan;Harris, Raymond C.
内皮一氧化氮合酶 (eNOS) 功能上显着的多态性和血管 eNOS 活性降低与人类糖尿病肾病 (DN) 增加有关，但 eNOS 缺乏在 DN 发展中的致病作用尚未得到证实。本研究描述了与 C57BLKS/J db/db 小鼠回交的 eNOS(-/-) 小鼠 DN 的严重程度。虽然高血糖的严重程度与 C57BLKS/J db/db 小鼠相似，但到 26 周时，eNOS(-/-) C57BLKS/J db/db 小鼠表现出严重的蛋白尿、小动脉透明变性、肾小球基底膜厚度增加、系膜扩张、系膜溶解以及局灶性节段性和早期结节性肾小球硬化。更值得注意的是，eNOS(-/-) C57BLKS db/db 的 GFR 降低至 < eNOS(+/+) C57BLKS db/db 水平的 50%，血清肌酐升高证实了这一点。总之，eNOS(-/-) db/db 小鼠提供了迄今为止已描述的最稳健的 11 型 DN 模型，并支持 eNOS 衍生的 NO 产生缺陷在 DN 发病机制中的作用。
Functionally significant polymorphisms in endothelial nitric oxide synthase (eNOS) and reduced vascular eNOS activity have been associated with increased human diabetic nephropathy (DN), but the pathogenic role of eNOS deficiency in the development of DN has not yet been confirmed. This study characterizes the severity of DN in eNOS(-/-) mice that were backcrossed to C57BLKS/J db/db mice. Although the severity of hyperglycemia was similar to C57BLKS/J db/db mice, by 26 wk, eNOS(-/-) C57BLKS/J db/db mice exhibited dramatic albuminuria, arteriolar hyalinosis, increased glomerular basement membrane thickness, mesangial expansion, mesangiolysis, and focal segmental and early nodular glomerulosclerosis. Even more remarkable, eNOS(-/-) C57BLKS db/db exhibited decreases in GFR to levels < 50% of that in eNOS(+/+) C57BLKS db/db, as confirmed by increased serum creatinine. In summary, eNOS(-/-) db/db mice provide the most robust model of type 11 DN that has been described to date and support a role for deficient eNOS-derived NO production in the pathogenesis of DN.