Involvement of asymmetric dimethylarginine (ADMA) in glomerular capillary loss and sclerosis in a rat model of chronic kidney disease (CKD).
Involvement of asymmetric dimethylarginine (ADMA) in glomerular capillary loss and sclerosis in a rat model of chronic kidney disease (CKD).
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DOI：
10.1016/j.lfs.2009.03.018
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发表时间：
2009-06
期刊：
影响因子：
6.1
通讯作者：
S. Ueda;S. Yamagishi;Yuriko Matsumoto;Y. Kaida;Ayako Fujimi-Hayashida;Kiyomi Koike;Hideharu Tanaka;K. Fukami;S. Okuda
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文献类型：
--
作者：
S. Ueda;S. Yamagishi;Yuriko Matsumoto;Y. Kaida;Ayako Fujimi-Hayashida;Kiyomi Koike;Hideharu Tanaka;K. Fukami;S. Okuda
AIMSAsymmetric dimethylarginine（ADMA）是一种内源性一氧化氮合酶抑制剂，已被报道为慢性肾脏病（CKD）进展的新标志物。我们最近发现，ADMA的积累可以触发肾小管周围毛细血管损失，从而有助于肾小管间质缺血和纤维化的大鼠模型的CKD。然而，ADMA对肾小球毛细血管损失和硬化的影响仍有待阐明。MAIN METHODS在这项研究中，我们调查是否降低ADMA的过表达的二甲基精氨酸二甲氨基水解酶（DDAH），降解ADMA的主要酶，可以改善肾小球毛细血管损失和硬化的大鼠模型CKD。在5/6肾大部切除术（Nx）后4周，尾静脉注射编码DDAH-1的重组腺病毒载体（Adv-DDAH）或表达细菌β-半乳糖苷酶的对照载体（Adv-LZ），或口服20 mg/kg/天肼苯哒嗪（Hyz）关键发现血浆ADMA水平与肾小球毛细血管数量减少以及NX大鼠肾小球硬化的严重程度。这些肾小球的变化进展在Adv-LZ或Hyz治疗的Nx-大鼠，而他们改善了DDAH overexpression. SIGNIFICANCE我们目前的数据表明，ADMA可能参与肾小球毛细血管损失和硬化，从而有助于CKD的进展。DDAH蛋白的替代或增强其活性可能成为治疗CKD的新策略。
AIMSAsymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, has been reported to be a novel marker for the progression of chronic kidney disease (CKD). We have recently found that accumulation of ADMA could trigger peritubular capillary loss, thus contributing to tubulointerstitial ischemia and fibrosis in a rat model of CKD. However, effects of ADMA on glomerular capillary loss and sclerosis remain to be elucidated.MAIN METHODSIn this study, we investigated whether lowering of ADMA by overexpression of dimethylarginine dimethylaminohydrolase (DDAH), a main enzyme that degrades ADMA, could ameliorate glomerular capillary loss and sclerosis in a rat model of CKD. Four weeks after 5/6 subtotal nephrectomy (Nx), animals were given tail vein injections with recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial β-galactosidase (Adv-LZ), or orally administered with 20 mg/kg/day of hydralazine (Hyz) which served as a blood pressure control model.KEY FINDINGSPlasma levels of ADMA were associated with decreased number of glomerular capillaries as well as severity of glomerular sclerosis in Nx-rats. These glomerular changes progressed in Adv-LZ- or Hyz-treated Nx-rats, while they were ameliorated by the treatment with DDAH overexpression.SIGNIFICANCEOur present data suggest that ADMA may be involved in glomerular capillary loss and sclerosis, thus contributing to the progression of CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of CKD.