Uneda Kazushi, Wakui Hiromichi, Maeda Akinobu, Azushima Kengo, Kobayashi Ryu, Haku Sona, Ohki Kohji, Haruhara Kotaro, Kinguchi Sho, Matsuda Miyuki, Ohsawa Masato, Minegishi Shintaro, Ishigami Tomoaki, Toya Yoshiyuki, Atobe Yoshitoshi, Yamashita Akio, Umemura Satoshi, Tamura Kouichi
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
J Am Heart Assoc. 2017 Jul 27;6(8):e006120. doi: 10.1161/JAHA.117.006120.
The kidney is easily affected by aging-associated changes, including glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Particularly, renal tubulointerstitial fibrosis is a final common pathway in most forms of progressive renal disease. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP), which was originally identified as a molecule that binds to AT1R, is highly expressed in the kidney. Previously, we have shown that ATRAP suppresses hyperactivation of AT1R signaling, but does not affect physiological AT1R signaling.
We hypothesized that ATRAP has a novel functional role in the physiological age-degenerative process, independent of modulation of AT1R signaling. ATRAP-knockout mice were used to study the functional involvement of ATRAP in the aging. ATRAP-knockout mice exhibit a normal age-associated appearance without any evident alterations in physiological parameters, including blood pressure and cardiovascular and metabolic phenotypes. However, in ATRAP-knockout mice compared with wild-type mice, the following takes place: (1) age-associated renal function decline and tubulointerstitial fibrosis are more enhanced; (2) renal tubular mitochondrial abnormalities and subsequent increases in the production of reactive oxygen species are more advanced; and (3) life span is 18.4% shorter (median life span, 100.4 versus 123.1 weeks). As a key mechanism, age-related pathological changes in the kidney of ATRAP-knockout mice correlated with decreased expression of the prosurvival gene, . On the other hand, chronic angiotensin II infusion did not affect renal sirtuin1 expression in wild-type mice.
These results indicate that ATRAP plays an important role in inhibiting kidney aging, possibly through sirtuin1-mediated mechanism independent of blocking AT1R signaling, and further protecting normal life span.
肾脏易受与衰老相关的变化影响，包括肾小球硬化、肾小管萎缩和间质纤维化。特别是，肾小管间质纤维化是大多数形式的进行性肾脏疾病的最终共同途径。血管紧张素II 1型受体（AT1R）相关蛋白（ATRAP）最初被鉴定为一种与AT1R结合的分子，在肾脏中高度表达。此前，我们已表明ATRAP可抑制AT1R信号的过度激活，但不影响生理性AT1R信号。
我们假设ATRAP在生理性衰老退变过程中具有新的功能作用，独立于对AT1R信号的调节。利用ATRAP基因敲除小鼠研究ATRAP在衰老中的功能作用。ATRAP基因敲除小鼠呈现正常的衰老相关外观，生理参数（包括血压以及心血管和代谢表型）无明显改变。然而，与野生型小鼠相比，ATRAP基因敲除小鼠出现以下情况：（1）与年龄相关的肾功能下降和肾小管间质纤维化更为严重；（2）肾小管线粒体异常及随后活性氧生成增加更为明显；（3）寿命缩短18.4%（中位寿命，100.4周对123.1周）。作为关键机制，ATRAP基因敲除小鼠肾脏中与年龄相关的病理变化与促生存基因表达降低相关。另一方面，慢性输注血管紧张素II对野生型小鼠肾脏沉默调节蛋白1的表达无影响。
这些结果表明，ATRAP在抑制肾脏衰老中起重要作用，可能通过沉默调节蛋白1介导的机制，独立于阻断AT1R信号，并进一步保护正常寿命。
