EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
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IF 4.7
Yanmin Zhang,Jianqiang Hu,Yan Zhang,Xiaolin Yang,Weihua Tong,Xinxin Ci
Background The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is a significant cause of kidney failure. Although the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been demonstrated to inhibit ferroptosis and alleviate cisplatin-induced AKI, the specific roles of Nrf2 and the alkaloid leonurine in modulating the AKI-CKD transition remain incompletely elucidated. Methods Murine and human proximal tubular epithelial cell models of the AKI-CKD transition were established using repeated low-dose cisplatin (RLDC) to investigate the roles of Nrf2 and leonurine in ferroptosis regulation and disease progression. Key results In mice, RLDC administration induced persistent tubular injury, ferroptosis, and progressive renal fibrosis. In HK-2 cells, RLDC triggered oxidative stress and ferroptosis. Although Nrf2 expression was transiently upregulated during the acute phase (4 weeks post-RLDC), it was downregulated by the chronic phase (8 weeks post-RLDC), correlating with impaired antioxidant capacity and exacerbated ferroptosis. Nrf2 knockout mice exhibited more severe oxidative damage, ferroptosis, and renal dysfunction following RLDC challenge. Pharmacological activation of Nrf2 by leonurine attenuated oxidative injury and ferroptosis and promoted tubular repair. Leonurine also suppressed the epithelial–mesenchymal transition and aberrant extracellular matrix deposition, ultimately mitigating renal fibrosis. The protective effects of leonurine were abolished in Nrf2 knockout mice. Conclusion These findings demonstrate that Nrf2 activation mitigates cisplatin-induced AKI-CKD transition by counteracting oxidative stress and ferroptosis, thereby attenuating renal fibrosis. Leonurine, as a potent Nrf2 activator, represents a promising therapeutic agent for preventing AKI-CKD transition.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
You Zhou,You Wu,Rui Zhu
Background Septic acute kidney injury (S-AKI) is a major cause of acute kidney injury (AKI), but no effective therapies exist to prevent or treat it. Although KLF6 is linked to various pathophysiological processes, its exact role in S-AKI is not yet fully understood. Methods The role of KLF was investigated using both the mouse CLP model and in vitro systems. To identify the transcriptional targets regulated by KLF6, ChIP-qPCR and luciferase reporter assays were carried out. Biochemical and cellular techniques were employed to assess cellular injury and lipid peroxidation levels. The extent of ferroptosis was evaluated through transmission electron microscopy (TEM). Results KLF6 levels were significantly increased in a renal IRI model. Knockdown of KLF6 using AAV9 reduced kidney injury in both in vitro and in vivo models, while KLF6 overexpression aggravated injury. Overexpression of KLF6 promoted ferroptosis, whereas its knockdown reduced lipid peroxidation and ferroptosis. KLF6 regulates NCOA4 expression by binding to its promoter, controlling ferroptosis. Knockdown of NCOA4 in vitro alleviated ferroptosis and cellular damage caused by KLF6 overexpression. Pharmacological inhibition of KLF6 reduced kidney injury and ferroptosis in S-AKI mice. Conclusion Our study uncovered a previously unrecognized role for KLF6 in S-AKI. By facilitating NCOA4 transcription, KLF6 intensified ferroptosis, which, in turn, aggravated septic AKI.
研究领域:
肾脏病学
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分子生物学
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病理生理学
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细胞生物学
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转录调控
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BIOELECTROCHEMISTRY
·
2025
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IF 4.5
Cheng Huang,Haowen Liu,Bao Jiang,Guoli Li,Xinlu Qin,Yinan Hua,Yongming Deng,Yicheng Wang,Lin Zhou
Acute kidney injury (AKI), a critical clinical syndrome marked by high incidence and mortality, is currently diagnosed mainly by serum creatinine (SCr) and blood urea nitrogen (BUN), which have high miss rates. This study innovatively proposes using urinary hydrogen peroxide (H 2 O 2 ) concentration changes, caused by renal oxidative stress in AKI, as a new indicator for AKI risk assessment and treatment monitoring. Results from in vitro and AKI animal models show this indicator can quickly monitor AKI onset and drug effects in mice via electrochemical sensing technology based on Bi 2 S 3 @Cu 0.1 , offering a novel approach for AKI diagnosis and rehabilitation monitoring.
研究领域:
生物医学工程
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肾脏病学
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电化学
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即时检测
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生物传感器
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TOXICOLOGY
·
2024
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IF 4.8
Jianan Zhai,Zhengguo Chen,Qi zhu,Zhifang Guo,Xiance Sun,Liping Jiang,Jing Li,Ningning Wang,Xiaofeng Yao,Cong Zhang,Haoyuan Deng,Shaopeng Wang,Guang Yang
Patulin (PAT), the most common mycotoxin, is widespread in foods and beverages which poses a serious food safety issue to human health. Our previous research confirmed that exposure to PAT can lead to acute kidney injury (AKI). Curcumin is the most abundant active ingredient in turmeric rhizome with various biological activities. The aim of this study is to investigate whether curcumin can prevent the renal injury caused by PAT, and to explore potential mechanisms. In vivo , supplementation with curcumin attenuated PAT-induced ferroptosis. Mechanically, curcumin inhibited autophagy, led to the accumulation of p62 and its interaction with Keap1, promoted the nuclear translocation of nuclear factor E2 related factor 2 (Nrf2), and increased the expression of antioxidant stress factors in the process of ferroptosis. These results have also been confirmed in HKC cell experiments. Furthermore, knockdown of Nrf2 in HKC cells abrogated the protective effect of curcumin on ferroptosis. In conclusion, we confirmed that curcumin mitigated PAT-induced AKI by inhibiting ferroptosis via activation of the p62/Keap1/Nrf2 pathway. This study provides new potential targets and ideas for the prevention and treatment of PAT.
研究领域:
毒理学
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药理学
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分子生物学
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食品安全
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Nano Today
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2025
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IF 10.9
Zhiwen Wang,Yue Xie,Mingcun Hu,Min Yang,Xingjian Zou,Chun Zhang
Effective countermeasures for acute kidney injury (AKI) remain unsatisfactory. During AKI progression, the timely and appropriate transition of macrophages from pro-inflammatory to anti-inflammatory states is critical for resolving acute inflammation and promoting tissue repair. Timely clearing of excess reactive oxygen species (ROS) and promotion of M2 polarization of macrophages are key determinants of AKI progression. Accordingly, we report an engineered renal-targeting nanozyme constructed from a novel two-dimensional nanomaterial, MXene nanosheets, via surface conjugation of the anticomplement component 5a aptamer (ac5a-Apt) and magnesium ions (Mg 2 + ). After AKI, the engineered nanozyme can not only target the kidneys but also navigates to inflammatory areas under the guidance of the ac5a-Apt, clear excessive ROS, inhibits the C5a-C5aR complement system activation and promote M2 polarization of macrophages. Importantly, after MXene reacts with ROS and degrades, the surface-loaded Mg 2+ is released, further suppressing the MAPK/ NF-κB signaling pathway to achieve sequential therapy. The engineered renal-targeting nanozyme offers a novel strategy based on ROS clearance and immune modulation for sequential AKI treatment.
研究领域:
医学
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生物材料学
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免疫学
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高影响因子
Materials Today Bio
·
2026
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IF 11
Ke Wang,Xing-chun Zhu,Yi Xia,Yan Yan,Jun-jie Ma,Jing-yi Xia,Yuan Xu,Meng-han He,Feng-le Guo,Wen-rui Wang,Li Ren,Cong-li Zhang
Acute kidney injury (AKI) caused by ischemia-reperfusion (IR) is an independent risk factor for the progression of chronic kidney disease (CKD), yet there is a lack of effective clinical interventions. Although butylphthalide (NBP) has been proven to have multi-organ protective potential, its rapid in vivo metabolism and low bioavailability limit its clinical application. To overcome these limitations, we rationally designed and synthesized a layered double hydroxide (LDHs)-based nanocarrier system for NBP delivery (LDHs@NBP) via hydrothermal co-precipitation. Comprehensive characterization confirmed successful nanocomplex formation. Critically, LDHs@NBP exhibited accelerated NBP release under mildly acidic conditions, matching the pathological acidosis of injured and fibrotic renal tubules—thereby achieving pH-responsive drug release. Using both an in vivo rat model of unilateral renal ischemia-reperfusion injury (uIRI) and an in vitro TGF-β1-stimulated HK-2 cell model, we demonstrated that LDHs@NBP significantly attenuated renal dysfunction, suppressed interstitial fibrosis, and improved mitochondrial function. Importantly, all protective effects were abolished upon co-treatment with Mdivi-1, confirming mitophagy as the central mechanistic axis. Collectively, this study successfully constructed LDHs@NBP nanocomplexes with pH-responsive drug release properties. This system enhances mitophagy by activating the PINK1-Parkin pathway, thereby effectively blocking AKI-CKD transition. It provides a new strategy with good translational prospects for clinical intervention in kidney diseases.
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高影响因子
PLoS One
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2026
·Vol. 21
·期 6
·e0351630
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IF 2.8
Jiaxin Peng,Jing Chen,Zhipu Qian,Mingzhang Han,Ling Chen
This study investigates the role and mechanism of ergothioneine (EGT) in mitigating the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). Using a cisplatin-induced mouse model of the AKI-to-CKD transition with EGT intervention, we combined histopathological examination, biochemical assays, and single-cell RNA sequencing (scRNA-seq) to provide evidence that EGT may improve renal function parameters and attenuate renal injury and fibrosis. scRNA-seq analysis revealed that EGT was associated with partial normalization of mitochondria-related gene expression in renal tubular epithelial cells, accompanied by enrichment of oxidative phosphorylation and electron transport chain pathways. Furthermore, our in vitro experiments supported a protective association of EGT with mitochondrial injury-related phenotypes in injured renal tubular epithelial cells, as indicated by reduced reactive oxygen species generation, partial preservation of mitochondrial membrane potential, and increased cellular ATP levels. These findings suggest that EGT may attenuate AKI-to-CKD progression in association with improved mitochondrial homeostasis, offering a potential therapeutic strategy for kidney diseases.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2022
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IF 5.195
Bin Du,Mengmeng Zhao,Yuehua Wang,Lili Yu,Qingqing Jiao,Yimeng Bai,Genyang Cheng
The oxidative stress and activation of the fibrosis pathway are essential pathological mechanisms of acute kidney injury (AKI). In this article, we designed a drug delivery system that could effectively improve oxidative stress and relieve fibrosis by the combination of precise targeting, solubilization, and reducing the toxicity of nano-transport system to strengthen the efficacy of AKI. Folic acid (FA) was used as the targeting molecule, and curcumin (Cur) and resveratrol (Res), which are Chinese medicine monomers with anti-inflammatory and antioxidant effects, were used as model drugs. Here, the targeting nanosystem (Cur/ [email protected] /TPGS) co-loaded with Cur and Res was successfully synthesized. Finally, the comprehensive therapeutic effect of the nanosystem was evaluated through the targeted and pharmacodynamic researches on the AKI models induced by cisplatin (CDDP) in vitro and in vivo . The studies in vitro proved that the nanosystem could not only specifically target HK-2 cells and promote the effective accumulation of Cur and Res in the kidney, but also effectively improve oxidative stress by eliminating reactive oxygen species (ROS), stabilizing mitochondrial membrane potential (MMP), and reducing the expression of apoptosis-related proteins. The studies in vivo showed that the nanosystem could effectively play the role of anti-oxidation, anti-inflammatory and alleviate fibrosis to reduce the apoptosis and necrosis of renal tubular cells. The nanosystem could coordinately repair damaged HK-2 cells by improving oxidative stress, inhibiting inflammation and tissue fibrosis, which provided a new idea for the treatment of AKI.
研究领域:
药学
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纳米技术
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药理学
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肾脏生理学
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治疗学
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高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2026
·
IF 9.6
Zhu Liu,Xinlin Liu,Liwan He,Shengzhe Zhuang,Zhaoyang Li,Shuaipeng Feng,Luping Sha,Siling Wang,Qinfu Zhao
Rhabdomyolysis-induced acute kidney injury (RM-AKI) is a life-threatening clinical condition characterized by excessive myoglobin release, leading to kidney tubular obstruction, oxidative stress, and iron-mediated lipid peroxidation. However, current therapies fail to effectively suppress oxidative stress cascades and lack kidney targeting. Herein, we developed a kidney-targeted nanodrug delivery system with multimodal antioxidant functionality (DFO@SOC) for RM-AKI therapy. Using antioxidant capacity as the decisive screening criterion, Se/S co -doped onion-derived carbon dots (SOC) were identified as the optimal nanocarrier through systematic natural polyphenol precursor selection and heteroatom-doping optimization. SOC exhibited pronounced superoxide dismutase-like and catalase-like activities. The iron chelator deferoxamine (DFO) was subsequently loaded onto SOC, yielding uniformly sized, negatively charged DFO@SOC nanoparticles. In vitro studies demonstrated efficient cellular uptake, robust intracellular scavenging of reactive oxygen species (ROS) and iron ions, and negligible cytotoxicity. In an RM-AKI mouse model, DFO@SOC selectively accumulated in injured kidneys. Notably, Sound Touch Visco-elastography (STVi) and Quantitative Tissue Scattering Coefficient (QTSC) enabled noninvasive and real-time evaluation of therapeutic efficacy with kidney stiffness decreasing significantly from ~14 to 7 kPa. Combined biochemical and histopathological analyses, DFO@SOC treatment significantly reduced Scr from ~193.31 to ~93.82 μmol/L and blood urea nitrogen (BUN) from ~52.99 to ~30.68 mmol/L compared to the model group. In summary, the synergistic antioxidant and iron-chelation effects of DFO and SOC, establishing DFO@SOC as a promising nanotherapeutic strategy for RM-AKI.
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International Journal of Pharmaceutics-X
·
2025
·
IF 6.4
Yinghan Wang,Shichao Liu,Feikai Zhu,Xuefei Wang,Hanyu Wang,Lin Long,Jun Xiao,Chuanlong Guo
Acute kidney injury (AKI) is a common and serious complication in clinical practice, especially when using chemotherapy drug cisplatin, which severely limits its anti-cancer efficacy. This study developed a novel nano delivery system (Fu-4-PBA/Po NPs) that combines fucoidan (Fu), endoplasmic reticulum stress (ERS) inhibitor 4-phenylbutyric acid (4-PBA), and natural antioxidant Polydatin (Po) to simultaneously alleviate cisplatin induced oxidative stress and ERS. The optimized Fu-4-PBA/Po NPs showed an average size of 102 ± 3.46 nm, a zeta potential of −16.5 ± 0.49 mV, and a high drug loading capacity of 10.34 ± 0.6 %. They exhibited excellent stability and a sustained release profile in vitro . In vitro results showed that treatment with Fu-4-PBA/Po NPs led to a marked increase in cell survival by 34.73 ± 3.54 percentage points compared to the model group, which had a survival rate of 45.97 ± 2.76 %. Furthermore, Fu-4-PBA/Po NPs effectively inhibited the accumulation of reactive oxygen species (ROS), mitochondrial membrane potential decline, and calcium ion release by targeting P-selectin and endoplasmic reticulum (ER) at the site of inflammation, and significantly alleviate cisplatin induced cell apoptosis. Mechanism studies showed that nanocomposites alleviate ERS by inhibiting the PERK-eIF2α-ATF4-CHOP pathway, while blocking the activation of the cGAS-STING pathway, thereby reducing DNA damage and inflammatory response. Pharmacokinetic studies showed that the peak concentration (Cmax) of the nanoparticles reached 2.2 times that of free Po, and the area under the curve (AUC) increased by 2 times. In animal studies, administration of Fu-4-PBA/Po NPs at a dose of 100 mg/kg notably ameliorated renal function, as indicated by reductions in serum creatinine (SCr) and blood urea nitrogen (BUN) levels by 84.3 % and 62.4 %, respectively, and also improved kidney histopathology. This study provided a dual targeted nano-delivery strategy for cisplatin induced AKI therapy, which has important clinical application potential.
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高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Ying Kong,Xu Chen,Feng Liu,Jiageng Tang,Yijing Zhang,Xiangxiang Zhang,Luyao Zhang,Tong Zhang,Yaqi Wang,Mengxiao Su,Qixin Zhang,Hanxiang Chen,Di Zhou,Fan Yi,Hong Liu,Yi Fu
As a central metabolic molecule, nicotinamide adenine dinucleotide (NAD + ) can potentially treat acute kidney injury (AKI) and chronic kidney disease (CKD); however, its bioavailability is poor due to short half-life, instability, the deficiency of targeting, and difficulties in transmembrane transport. Here we designed a physiologically adaptive gallic acid-NAD + nanoparticle, that had ultrasmall size and pH-responsiveness, passed through the glomerular filtration membrane to reach injured renal tubules, and efficiently delivered NAD + into the kidneys. With an effective accumulation in the kidneys, it restored renal function, immune microenvironment homeostasis, and mitochondrial homeostasis of AKI mice via the NAD + -Sirt1 axis, and exerted strong antifibrotic effects on the AKI-to-CKD transition by inhibiting TGF-β signaling. It also exhibited excellent stability, biodegradable, and biocompatible properties, ensuring its long-term safety, practicality, and clinical translational feasibility. The present study shows a potential modality of mitochondrial repair and immunomodulation through nanoagents for the efficient and safe treatment of AKI and CKD. This article is protected by copyright. All rights reserved
研究领域:
肾病学
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药学
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生物医学工程
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分子生物学
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高影响因子
Journal of Inflammation Research
·
2024
·
IF 4.2
Liu Yang,Yan Xu,Jian Pan,Renjie Li,Chao Lan,Dongshan Zhang
Background Acute kidney injury (AKI) is associated with higher perioperative mortality and morbidity, as well as increased medical expenses. The molecular mechanisms underlying ischemia-reperfusion (I/R)-induced AKI remain unclear.Methods and Results We applied an RT-qPCR assay to measure the expression of mmu-lncRNA129814, hsa-lncRNA582795, and miRNA-494-5p, immunoblotting to detect IL-1α and cleaved caspase-3 expression, and TUNEL staining and flow cytometry (FCM) to evaluate apoptosis. The experiments were conducted using BUMPT and HK-2 cells, as well as C57BL/6J mice. Mechanistically, mmu-lncRNA129814 could sponge miRNA-494-5p and upregulate IL-1α expression to promote cell apoptosis. Furthermore, knockdown of mmu-lncRNA129814 ameliorated I/R-induced progression of AKI by targeting the miRNA-494-5p/IL-1α pathways. Interestingly, hsa-lncRNA582795, a homolog of mmu-lncRNA129814, also promoted I/R-stimulated HK-2 cell apoptosis and AKI progression by regulating the miRNA-494-5p/IL-1α axis. Finally, we found that patients with I/R-induced AKI exhibited significantly elevated plasma and urinary levels of hsa-lncRNA582795 compared to those who underwent ischemia-reperfusion without developing AKI. Spearman’s test demonstrated a significant correlation between serum creatinine and plasma hsa-lncRNA582795 in I/R patients. Plasma hsa-lncRNA582795 showed high sensitivity but low specificity (86.7%) compared to urinary hsa-lncRNA582795.Conclusion The mmu-lncRNA129814/hsa-lncRNA582795/miRNA-494-5p/IL-1α axis was found to modulate the progression of ischemic AKI, and hsa-lncRNA582795 could act as a diagnosis biomarker and potential therapy target of I/R-induced AKI.
研究领域:
肾病学
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分子生物学
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医学遗传学
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高影响因子
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