Angiostatin production increases in response to decreased nitric oxide in aging rat kidney
Angiostatin production increases in response to decreased nitric oxide in aging rat kidney
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DOI：
10.1038/labinvest.2012.171
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发表时间：
2013-03-01
影响因子：
5
通讯作者：
Kashihara, Naoki
中科院分区：
文献类型：
--
作者：
Satoh, Minoru;Kidokoro, Kengo;Kashihara, Naoki
间质性纤维化的发展随着年龄的增长而发生。与肾微血管的进行性损失相关的血管生成受损被认为是年龄相关性肾病的原因。然而，衰老肾脏毛细血管损失的机制尚未完全阐明。血管抑制素是纤溶酶原的一个含有Kringle的片段，是体内血管生成的有效抑制剂。血管抑素的生成是否在衰老的肾脏中增加还没有研究。我们检查了4，10，16，和24个月大的Sprague-Dawley大鼠血管抑素的生产，发现血管抑素的生产增加老年大鼠。组织蛋白酶D的蛋白表达和活性增加，血管生成抑制素的酶，在老年大鼠。在老化的肾脏中，一氧化氮（NO）的可用性降低。为探讨NO在血管抑素生成中的作用，用L-NG-硝基精氨酸甲酯（L-NAME）处理人脐静脉内皮细胞。L-NAME处理的细胞表现出增加的组织蛋白酶D活性和血管抑素生产。对于体内实验，16至18个月大的大鼠用L-NAME或吗西多明治疗3个月。血管生成抑制素的增加，L-NAME治疗的肾脏，伴随着增加组织蛋白酶D活性。与此相反，血管生成抑制素减少吗西多明治疗的肾脏，伴随着组织蛋白酶D活性降低。总之，组织蛋白酶D在衰老大鼠肾脏中的血管抑素生成增加。NO生成减少激活组织蛋白酶D活性。血管生成抑制素的增加可能与衰老大鼠肾脏毛细血管损失和间质损伤有关。实验室调查（2013）93，334-343; doi：10.1038/labinvest.2012.171; 2013年1月7日在线发表
The development of interstitial fibrosis occurs with aging. Impaired angiogenesis, associated with progressive loss of the renal microvasculature, is thought to be a cause of age-related nephropathy. However, the mechanism of capillary loss in aging kidney has not been fully elucidated. Angiostatin is a kringle-containing fragment of plasminogen and is a potent inhibitor of angiogenesis in vivo. Whether angiostatin generation is increased in the aging kidney has not been investigated. We examined 4, 10, 16, and 24-month-old Sprague-Dawley rats for angiostatin production and found that angiostatin generation was increased in aged rats. The protein expression and the activity of cathepsin D the enzyme for angiostatin production-were increased in aged rats. In the aging kidney, nitric oxide (NO) availability is decreased. To investigate the role of NO in angiostatin production, human umbilical vein endothelial cells were treated with L-NG-nitroarginine methyl ester (L-NAME). L-NAME-treated cells showed increased cathepsin D activity and angiostatin production. For in vivo experiments, 16- to 18-month-old rats were treated with L-NAME or molsidomine for 3 months. Angiostatin production was increased in L-NAME-treated kidney, accompanied by increased cathepsin D activity. In contrast, angiostatin production was decreased in molsidomine-treated kidney, accompanied by decreased cathepsin D activity. In conclusion, angiostatin generation by cathepsin D was increased in the aging rat kidney. Decreased NO production activated cathepsin D activity. Increased angiostatin production may be related to capillary loss and interstitial damage in the aging rat kidney. Laboratory Investigation (2013) 93, 334-343; doi:10.1038/labinvest.2012.171; published online 7 January 2013