Yabuuchi Nozomi, Sagata Masataka, Saigo Chika, Yoneda Go, Yamamoto Yuko, Nomura Yui, Nishi Kazuhiko, Fujino Rika, Jono Hirofumi, Saito Hideyuki
Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
Int J Mol Sci. 2016 Dec 23;18(1):11. doi: 10.3390/ijms18010011.
High mortality of acute kidney injury (AKI) is associated with acute lung injury (ALI), which is a typical complication of AKI. Although it is suggested that dysregulation of lung salt and water channels following AKI plays a pivotal role in ALI, the mechanism of its dysregulation has not been elucidated. Here, we examined the involvement of a typical oxidative stress-inducing uremic toxin, indoxyl sulfate (IS), in the dysregulation of the pulmonary predominant water channel, aquaporin 5 (AQP-5), in bilateral nephrectomy (BNx)-induced AKI model rats. BNx evoked AKI with the increases in serum creatinine (SCr), blood urea nitrogen (BUN) and serum IS levels and exhibited thickening of interstitial tissue in the lung. Administration of AST-120, clinically-used oral spherical adsorptive carbon beads, resulted in a significant decrease in serum IS level and thickening of interstitial tissue, which was accompanied with the decreases in IS accumulation in various tissues, especially lung. Interestingly, a significant decrease in AQP-5 expression of lung was observed in BNx rats. Moreover, the BNx-induced decrease in pulmonary AQP-5 protein expression was markedly restored by oral administration of AST-120. These results suggest that BNx-induced AKI causes dysregulation of pulmonary AQP-5 expression, in which IS could play a toxico-physiological role as a mediator involved in renopulmonary crosstalk.
急性肾损伤（AKI）的高死亡率与急性肺损伤（ALI）相关，ALI是AKI的一种典型并发症。尽管有研究表明，AKI后肺脏盐和水通道的失调在ALI中起关键作用，但其失调机制尚未阐明。在此，我们研究了一种典型的诱导氧化应激的尿毒症毒素——硫酸吲哚酚（IS），在双侧肾切除（BNx）诱导的AKI模型大鼠中，对肺脏主要水通道水通道蛋白5（AQP - 5）失调的影响。BNx诱导了AKI，表现为血清肌酐（SCr）、血尿素氮（BUN）和血清IS水平升高，且肺间质组织增厚。给予临床上使用的口服球形吸附碳珠AST - 120后，血清IS水平显著降低，间质组织增厚减轻，同时各种组织尤其是肺中的IS蓄积减少。有趣的是，在BNx大鼠中观察到肺组织中AQP - 5表达显著降低。此外，口服AST - 120可明显恢复BNx诱导的肺组织AQP - 5蛋白表达降低。这些结果表明，BNx诱导的AKI导致肺组织AQP - 5表达失调，其中IS可能作为肾肺相互作用的介质发挥毒理生理作用。
