Cell communication and signaling : CCS · 2025
The Roxadustat (FG-4592) ameliorates tubulointerstitial fibrosis by promoting intact FGF23 cleavage.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Wang Jing, Li Zuo-Lin, Zhou Yan, Li Zhong-Tang, Tu Yan, Hu Xin-Hui, Zhu Jin-Hua, Liu Bi-Cheng, Liu Hong
Аннотация
BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) represents a novel therapeutic approach for renal anemia, a prevalent complication of chronic kidney disease (CKD). However, the effects of HIF-PHI on renal functional outcomes remain poorly characterized. Here, the potential effects of FG-4592, an orally administered HIF-PHI, on renal fibrosis were explored systematically.
METHODS: In this study, a CKD rat model was established through subtotal 5/6 nephrectomy. Rats were administered either FG-4592 or vehicle control via oral gavage three times weekly for 12 consecutive weeks. Additionally, recombinant FGF23 was continuously delivered via subcutaneously implanted Alzet osmotic minipumps for 28 days.
RESULTS: Interestingly, we found that CKD-induced anemia was significantly ameliorated in CKD rats with FG-4592 treatment. Meanwhile, markedly alleviated histopathological changes and renal tubulointerstitial fibrosis (TIF) were observed in rats with FG-4592 administration. Notably, serum levels of intact FGF23 (iFGF23) were significantly reduced following FG-4592 administration in CKD rats. This finding was subsequently validated in CKD patients receiving Roxadustat therapy. Mechanistically, we illustrated that inhibition of the iFGF23-WNT5A pathway was the exact mechanism by which FG-4592 ameliorated TIF. Further, we also demonstrated that transcriptional activation of Furin enzyme was the exact molecular mechanism for FG-4592-mediated iFGF23 cleavage.
CONCLUSIONS: FG-4592 attenuates TIF through Furin-mediated proteolytic cleavage of iFGF23. These findings provide novel mechanistic insights into HIF-PHI-mediated renal protection and establish a theoretical framework for clinical translation.
METHODS: In this study, a CKD rat model was established through subtotal 5/6 nephrectomy. Rats were administered either FG-4592 or vehicle control via oral gavage three times weekly for 12 consecutive weeks. Additionally, recombinant FGF23 was continuously delivered via subcutaneously implanted Alzet osmotic minipumps for 28 days.
RESULTS: Interestingly, we found that CKD-induced anemia was significantly ameliorated in CKD rats with FG-4592 treatment. Meanwhile, markedly alleviated histopathological changes and renal tubulointerstitial fibrosis (TIF) were observed in rats with FG-4592 administration. Notably, serum levels of intact FGF23 (iFGF23) were significantly reduced following FG-4592 administration in CKD rats. This finding was subsequently validated in CKD patients receiving Roxadustat therapy. Mechanistically, we illustrated that inhibition of the iFGF23-WNT5A pathway was the exact mechanism by which FG-4592 ameliorated TIF. Further, we also demonstrated that transcriptional activation of Furin enzyme was the exact molecular mechanism for FG-4592-mediated iFGF23 cleavage.
CONCLUSIONS: FG-4592 attenuates TIF through Furin-mediated proteolytic cleavage of iFGF23. These findings provide novel mechanistic insights into HIF-PHI-mediated renal protection and establish a theoretical framework for clinical translation.