You Xiaoe, Guo Baochun, Wang Zhen, Ma Hualin, Zhang Xinzhou
The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, 518020, Guangdong, China.
Department of Nephrology, Shenzhen Peoples Hospital The Second Clinical Medical College, The First Affiliated Hospital, Jinan University, Southern University of Science and Technology, Shenzhen, 518020, Guangdong, China.
Clin Proteomics. 2022 Jun 11;19(1):21. doi: 10.1186/s12014-022-09358-w.
Roxadustat is a new oral anti-renal anemia medication that works by stabilizing hypoxia-inducible factor (HIF) which can activate the expression of more than 100 genes in addition to genes related to anemia. However, the more potential molecular targets of roxadustat are not completely clear. Therefore, it is essential to further reveal its molecular targets to guide its clinical applications.
We performed label-free quantification and LC-MS/MS to study the proteomic alterations in serum exosome of renal anemia patients before and after roxadustat therapy. Results were validated by PRM.
A total of 30 proteins were significantly changed after treatment with roxadustat. Among these proteins, 18 proteins were up-regulated (and 12 were down-regulated). The results are statistically significant (P < 0.05). Then, we validated the result by PRM, the results confirmed that TFRC, HSPA8, ITGB3, COL1A2, and YWHAZ were markedly upregulated, while ITIH2 and CFH were significantly downregulated upon treatment with roxadustat.
TFRC and HSPA8 could be an important target of the action of roxadustat, and roxadustat may increase cardiovascular risk through its influence on platelet activation. Our results provide a theoretical basis for its wider clinical application and preventing expected side effects.
罗沙司他是一种新型口服抗肾性贫血药物，其作用机制是稳定缺氧诱导因子（HIF），HIF除了激活与贫血相关的基因外，还能激活100多个基因的表达。然而，罗沙司他更多潜在的分子靶点尚不完全清楚。因此，进一步揭示其分子靶点对于指导其临床应用至关重要。
我们采用无标记定量和液相色谱-串联质谱法研究罗沙司他治疗前后肾性贫血患者血清外泌体中的蛋白质组学变化。结果通过平行反应监测（PRM）进行验证。
罗沙司他治疗后共有30种蛋白质发生显著变化。其中，18种蛋白质上调（12种下调）。结果具有统计学意义（P < 0.05）。然后，我们通过PRM验证结果，结果证实，罗沙司他治疗后，转铁蛋白受体（TFRC）、热休克蛋白A8（HSPA8）、整合素β3（ITGB3）、Ⅰ型胶原蛋白α2链（COL1A2）和14-3-3ζ蛋白（YWHAZ）明显上调，而富含亮氨酸α2糖蛋白2（ITIH2）和补体因子H（CFH）显著下调。
TFRC和HSPA8可能是罗沙司他作用的重要靶点，罗沙司他可能通过影响血小板活化增加心血管风险。我们的结果为其更广泛的临床应用和预防预期副作用提供了理论依据。
