Cell Communication and Signaling
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2025
·Vol. 23
·期 1
·1-17
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IF 8.9
Wang Jing,Li Zuo-Lin,Zhou Yan,Li Zhong-Tang,Tu Yan,Hu Xin-Hui,Zhu Jin-Hua,Liu Bi-Cheng,Liu Hong
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.
研究领域:
肾脏病学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF BONE AND MINERAL RESEARCH
·
2025
·
IF 5.9
Zhu Yu-yu,Zhang Dan-feng,Tong Xiao-wen,Zhao Wen-man,Shi Rui,Li Xun-liang,Wang Zhi-juan,Wang De-guang
AimTo determine the effects of roxadustat on calcification when treating renal anemia in end-stage kidney disease (ESKD) patients.MethodsA prospective cohort study enrolled participants with ESKD that either received roxadustat or no roxadustat treatment. The primary outcome was the change in the degree of hydroxyapatite (HAP) crystals deposition. The secondary outcome was calcification propensity, a measure of calcification, allowing an evaluation of the conversion process from primary to secondary calciprotein particles.ResultsA total of 205 patients were enrolled, and 187 (91.2%) completed follow-up for inclusion in the analysis and were divided into the roxadustat group (n = 92) and the control group (n = 95) based on whether or not they were taking roxadustat regularly over a 6-month period. After roxadustat administration for 6 months, patients exhibited increases in total red blood cell counts, hematocrit, hemoglobin, calcium, total ferritin binding, iFGF23, SPP24, and calcification propensity relative to pre-treatment levels. No significant differences were observed in patients who were not treated with roxadustat. The deposition degree of HAP crystals increased by 5% and 0.01% following treatment with roxadustat in the roxadustat group and control group, respectively. Linear regression analysis found that the use of roxadustat was an independent risk factor for calcification propensity and changes in the degree of HAP crystals deposition.ConclusionRoxadustat treatment may increase iFGF23, SPP24, and calcification propensity in patients with ESKD when treating these patients for renal anemia. Therefore, the clinicians should aware of this risk when treating patients with PHIs.
研究领域:
医学
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肾脏病学
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药理学
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PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2023
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IF 4.5
Yujing Wang,Min Xiao,Feng Cai,Yang Li,Tianli Shi,Xiaoyan Zhou,Shuhong Tian,Denggao Huang
Vascular calcification (VC) is a common complication of chronic kidney disease (CKD). VC is a gene-regulated process similar to osteogenic differentiation. There are still no convincing schemes to prevent and reduce the development of VC. It has been reported that hypoxia-inducing factor 1α (HIF-1α) and endothelin-1(ET-1) are related to VC. In this study, we found that the expression of ET-1 and HIF-1α was enhanced after VC, the interaction between HIF-1α and ET-1 was confirmed by CO-IP and luciferase experiments. We found that ET-1 was an upregulated differential gene of calcified vascular smooth muscle cells (VSMCs) through gene sequencing. However, hypoxia-inducing factor 2α (HIF-2α) and HIF-1α have antagonistic effects on each other. HIF-1α is a pro-inflammatory cytokine, and HIF-2α can improve inflammation and fibrosis. Roxadustat, as a selective PHD3 inhibitor, preferentially activates HIF-2α. It is still unclear whether roxadustat improves VC in CKD by regulating the expression of HIF-2α/HIF-1α. Alizarin red staining and western blot as well as immunohistochemical results showed that roxadustat could significantly reduce the degree of vascular and VSMCs calcification in CKD rats. Serum HIF-1α and ET-1 were significantly decreased after roxadustat treatment. In addition, western blot results showed that roxadustat could decrease the expression of HIF-1α and ET-1 in vascular tissues and calcified VSMC, but HIF-2α expression significantly increased. Interestingly, our study confirmed that activation of HIF-1α or inhibition of HIF-2α reversed the ameliorating effect of roxadustat on VC, proving that the effect mediated by roxadustat is HIF-2α/HIF-1α dependent. We have demonstrated for the first time that roxadustat improves VC in CKD rats by regulating HIF-2α/HIF-1α, thus providing a new idea for the application of roxadustat in VC of CKD.
研究领域:
药理学
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肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
RENAL FAILURE
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2026
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IF 3.8
Jia Wang,Jin-Wei E.,Jiong Zhang
Roxadustat (ROX) has a protective action against contrast-induced acute kidney injury (CI-AKI). Excessive production of reactive oxygen species (ROS) plays a significant role in exacerbating the deterioration of renal function. Notably, activation of Nrf2/HO-1 signaling can reduce ROS production. We constructed a mouse model of CI-AKI by iohexol injection. The effect of ROX on CI-AKI was assessed by measuring serum blood urea nitrogen (BUN) and creatinine (Cr), evaluating renal histopathology, and analyzing the expression level of Nrf2 and HO-1. Additionally, levels of ROS, malondialdehyde (MDA), proinflammatory cytokines (IL-6, TNF-α, and IL-1β), as well as the activities of antioxidant kinases superoxide dismutase (SOD) and glutathione (GSH), were examined. The results showed that ROX significantly suppresses the iohexol-induced decline in the activity of antioxidant enzymes, increases the levels of ROS, MDA, Cr, IL-6, IL-1β, BUN and TNF-α, and attenuates renal pathological injury. Furthermore, ROX enhanced the iohexol–induced increase in Nrf2 and HO-1 expression. However, these effects of ROX on CI-AKI were abolished by ML-385, a Nrf2 inhibitor. Our findings indicate ROX attenuates CI-AKI by down-regulating inflammation and restoring the balance between oxidative stress and anti-oxidant defenses. This may involve the activation of the Nrf2/HO-1 signaling pathway to clear excessive ROS.
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DOI
PubMed
高影响因子
CRYSTAL GROWTH & DESIGN
·
2023
·
IF 3.8
Mengwei Wang,Qiuyan Ran,Songgu Wu,Dandan Han,Junbo Gong
The use of polymers is an increasingly common approach to prevent crystallization from the supersaturated solutions for enhanced bioavailability of poorly water-soluble drugs. In this study, roxadustat (RST), a water-insoluble drug, was selected as a model substance. We quantified the effectiveness of three polymers with different types of hydrogen bonding moieties, polyvinylpyrrolidone (PVP), poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA), and hydroxypropyl methylcellulose (HPMC), on nuclear inhibition of RST and found that the inhibitory effect was HPMC > PVPVA > PVP. In the absence of polymers, the induction time of RST in the RST supersaturated solution was 1.5 min, while in the presence of HPMC, the induction time of RST was as long as 84.5 min. Simulation by Material Studio suggested that the compatibility and bonding energy between the polymers and RST showed a strongly positive correlation with the effectiveness of polymers. The combined inhibitory effect of hydrogen bonding and hydrophobic interaction between RST and polymers were revealed by FTIR, 1H NMR spectroscopy, and nuclear Overhauser effect spectroscopy. Moreover, the obtained amorphous-state RST in RST–polymer amorphous solid dispersions achieved improved solubility than that of crystalline RST, and the dissolved amorphous RST maintained the supersaturation for 6 h in the dissolution test without the decrease in concentration due to nucleation and crystal growth.
研究领域:
药剂学
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药物化学
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高影响因子
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