Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointerstitial fibrosis in a rat model of chronic kidney disease
Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointerstitial fibrosis in a rat model of chronic kidney disease
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DOI：
10.1681/asn.2006070696
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发表时间：
2007-05-01
影响因子：
13.6
通讯作者：
Okuda, Seiya
中科院分区：
文献类型：
--
作者：
Matsumoto, Yuriko;Ueda, Seiji;Okuda, Seiya
不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶抑制剂，主要由二甲基精氨酸二甲氨基水解酶（DDAH）降解。最近报道，在慢性肾脏病（CKD）的实验模型中，DDAH表达减少可能导致ADMA蓄积和随后的血压升高。ADMA也是CKD进展的有力预测因素。然而，ADMA-DDAH在CKD发病机制中的作用仍有待阐明。本研究在大鼠残肾模型中研究DDAH诱导的ADMA降低对肾功能和病理学的影响。在6/5肾大部切除术（Nx）后4周，大鼠尾静脉注射编码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）或口服肼屈嗪（Hyz）20 mg/kg/d，作为血压控制模型。与Adv-LZ或Hyz给药相比，Adv-DDAH可降低血浆ADMA水平，并抑制肾功能不全的恶化。血浆ADMA水平与Nx大鼠肾小管周围毛细血管数量减少、肾小管间质纤维化增加和蛋白尿水平相关。这些变化在Adv-LZ或Hyz治疗的Nx大鼠中进展，DDAH过表达可改善这些变化。此外，TGF-β的半定量逆转录-PCR和免疫组化显示，Adv-DDAH抑制Nx大鼠TGF-β表达的上调。这些数据表明，ADMA可能参与肾小管周围毛细血管损失和肾小管间质纤维化，从而促进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。
Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). It was recently reported that reduced DDAH expression could contribute to ADMA accumulation and subsequent elevation of BP in an experimental model of chronic kidney disease (CKD). ADMA is a strong predictor of the progression of CKD as well. However, a role for the ADMA-DDAH in the pathogenesis of CKD remains to be elucidated. This study investigated the effects of DDAH-elicited ADMA lowering on renal function and pathology in a rat remnant kidney model. Four weeks after five-sixths subtotal nephrectomy (Nx), the rats were given tail-vein injections of recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial beta-galactosidase (Adv-LZ) or orally administered 20 mg/kg per d hydralazine (Hyz), which served as a BP control model. In comparison with Adv-LZ or Hyz administration, Adv-DDAH decreased plasma levels of ADMA and inhibited the deterioration of renal dysfunction. Plasma levels of ADMA were associated with decreased number of peritubular capillaries, increased tubulointerstitial fibrosis, and proteinuria levels in Nx rats. These changes were progressed in Adv-LZ- or Hyz-treated Nx rats, which were ameliorated by DDAH overexpression. In addition, semiquantitative reverse transcriptase-PCR and immunohistochemistry for TGF-beta revealed that Adv-DDAH inhibited upregulation of TGF-beta expression in Nx rats. These data suggest that ADMA may be involved in peritubular capillary loss and tubulointerstitial fibrosis, thereby 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.