NanoImpact
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2025
·
IF 5.5
Yingqi Wang,Shen Zhao,Nengyi Ni,Hongyu Chen,Wenjian Zhao,Kuoran Xing,Xiao Sun,Xiuli Jing
Nanomaterials have been widely used in various fields due to their excellent properties. However, the long-term exposure of humans to the environment of nanomaterials may lead to some pathological and physiological changes, such as the disruption of the glomerular filtration barrier (GFB), which can lead to high permeability and filterable albumin. Glomerular albuminuria results from the failure of the GFB, which may be caused by activation of the Notch1 signaling pathway. The reduction of glomerular endocalyx results in the level of VE-cadherin being diminished between endothelial cells, leading to leakiness in the endothelium. As previously discovered, certain nanoparticles, such as negatively charged gold nanoparticles of appropriate size, can directly facilitate the onset of endothelial leakiness through disrupting connections between vascular endothelial cells, in a process known as nanomaterial-induced endothelial leakiness (NanoEL). In this study, the negatively charged Au NPs with a diameter of 20 nm were synthesized first. Through the co-incubation of 20 nm Au NPs with a single layer of continuous HUVECs, we revealed that the synthesized 20 nm Au NPs could break the tight junctions and cause endothelial cell leakage. In addition, by constructing an endothelial leakage model between glomerular vascular endothelial cells, we confirmed that 20 nm Au NPs can generate NanoEL between glomerular endothelial cells, involving downstream processes coinciding with Notch signaling activation, resulting in the increase of urinary protein. The results of this study add to the understanding of the behaviour of nanoparticles in complex biological systems.
研究领域:
医学
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毒理学
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纳米生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Meng-xiao Wang,Ke-ke Luo,Meng-yao Tian,Wen-ya Gao,Shan Jiang,Yan Zhang,Jian Yang,Nan Si,Shi-lan Ding,Xiao-lu Wei,Yu-yang Liu,Bao-lin Bian,Yan-yan Zhou,Hong-jie Wang
The diagnosis and treatment of chronic glomerulonephritis (CGN) during childhood pose distinct challenges. Acteoside (ACT) is the primary active ingredient extracted from the leaves of Rehmannia glutinosa by our research group, accounting for 2.15 %, which possess multiple biological activities, especially for nephropathy treatment. However, its mechanism intervention on CGN in children remains obscure. In this study, we established a model of purinomycin aminonucleoside (PAN)-induced CGN in childhood rats to assess the potential therapeutic effect and underlying mechanisms of ACT. Leveraging network pharmacology and multi-omics technology, we delved into the effects and mechanisms of ACT intervention on CGN. And these findings were further corroborated through qRT-PCR, western blot and targeted metabolomics. Our results demonstrated that ACT had significantly efficient in the treatment of CGN in childhood rats by improving the key indicators and pathological changes. Further, ACT could significantly regulate differences in endogenous small molecules and genes based on non-target metabolomics and transcriptomics. Meanwhile, target capture analysis found the crucial targets of ACT treatment in CGN. Integrated analysis of multi-omics study indicated that PI3K/Akt signaling pathway and its downstream amino acid metabolism were significantly enriched, hinting at the essential regulatory pathway for ACT in treating of CGN. Finally, through qRT-PCR, western blot and targeted metabolomics, it was verified that ACT could ameliorate CGN through Cxcr4-PI3K-Akt-eNOS signaling pathway, thereby regulating amino acid metabolism. The collective results were consistent with those of multi-omics analysis. Our study illuminated that ACT had notable curative effect on CGN rats, and preliminarily elucidated its mechanism of action. Our research will provide solid basis for the treatment of chronic glomerulonephritis in children with ACT and developing it into innovative traditional Chinese medicine.
研究领域:
药理学
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分子生物学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-18
·
IF 10.2
Chen Wei,Wang Bing,Liang Shanshan,Wang Meng,Zheng Lingna,Xu Si,Wang Jiali,Fang Hao,Yang Pu,Feng Weiyue
Background Renal excretion is one of the major routes of nanomaterial elimination from the body. Many previous studies have found that graphene oxide nanosheets are excreted in bulk through the kidneys. However, how the lateral size affects GO disposition in the kidneys including glomerular filtration, active tubular secretion and tubular reabsorption is still unknown.Results The thin, two-dimensional graphene oxide nanosheets (GOs) was observed to excrete in urine through the kidneys, but the lateral dimension of GOs affects their renal clearance pathway and renal injury. The s-GOs could be renal excreted via the glomerular filtration, while the l-GOs were predominately excreted via proximal tubular secretion at a much faster renal clearance rate than the s-GOs. For the tubular secretion of l-GOs, the mRNA level of basolateral organic anion transporters Oat1 and Oat2 in the kidney presented dose dependent increase, while no obvious alterations of the efflux transporters such as Mdr1 and Mrp4 mRNA expression levels were observed, suggesting the accumulation of l-GOs. During the GO renal elimination, mostly the high dose of 15 mg/kg s-GO and l-GO treatment showed obvious kidney injuries but at different renal compartment, i.e., the s-GOs induced obvious glomerular changes in podocytes, while the l-GOs induced more obvious tubular injuries including necrosis of renal tubular epithelial cells, loss of brush border, cast formation and tubular dilatation. The specifically tubular injury biomarkers KIM1 and NGAL were shown slight increase with mRNA levels in l-GO administrated mice.Conclusion sThis study shows that the lateral size of GOs affected their interactions with different renal compartments, renal excretion pathways and potential kidney injuries.
研究领域:
纳米技术
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毒理学
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药代动力学
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2015
·Vol. 11
·期 6
·4321-4326
·
IF 1.554
Lei Lan,Yongsheng Han,Wei Ren,Jielong Jiang,Peng Wang,Zhao Hu
The present study aimed to determine the molecular mechanisms leading to the production of advanced glycation end‑products (AGEs) and their effect on the morphology and function of rat glomerular capillary endothelial cells (GECs). Primary rat GECs were treated with AGE‑modified human serum albumin (AGE‑HSA) and divided into groups according to AGE concentration and treatment time. The structure and distribution of cytoskeletal protein F‑actin and the cortical actin binding protein, cortactin, were analyzed using immunofluorescence and confocal microscopy. As the Ras‑related C3 botulinum toxin substrate 1 (Rac1) signaling pathway was previously identified to be involved in mediating the contraction of endothelial actin‑myosin activity, Rac1 was examined subsequent to treatment of the cells with the Rac1 agonist 2'‑O‑methyladenosine‑3',5'‑cyclic monophosphate (O‑Me‑cAMP) for 1 h using a pull‑down assay. Cell permeability was determined by the leakage rate of a fluorescein isothiocyanate fluorescent marker protein. AGE‑HSA treatment resulted in alterations in the structure and distribution of F‑actin and cortactin in a dose‑ and time‑dependent manner, while no effect was observed with HSA alone. The effect of AGE on the cytoskeleton was inhibited by the addition of O‑Me‑cAMP. AGE‑HSA significantly reduced the level of Rac1 activity (P<0.05); however, no effect was observed on total protein levels. Furthermore, AGE‑HSA treatment led to a significant increase in the permeability of endothelial cells (P<0.01), which was inhibited by O‑Me‑cAMP (P<0.01). The Rac1 signaling pathway is thus suggested to serve an important function in mediating AGE‑induced alterations in GEC morphology and function.
研究领域:
分子生物学
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医学
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细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Zhengqi Zha,Xiaoning Wang,Guoqing Wang,Hongping Yin,Hang Wang
Acetic acid has been shown to be effective in chronic kidney disease (CKD). However, it is a low-molecular-weight compound that allows it to be absorbed in the upper digestive tract so that it cannot function in colon. To overcome these deficiencies, an acetate-releasing xylan derivative, xylan acetate ester (XylA), was synthesized and selected in this study for its potential in the treatment of CKD. IR, NMR and HPGPC were used to characterize the structure of XylA and its antinephritic effects was evaluated in vivo. The results showed that acetate was successfully grafted onto the C-2 and C-3 positions of xylan and with a molecular weight at 69157 Da. XylA treatments could relieve the symptoms of CKD in an adenine-induced chronic renal failure (CRF) model and an adriamycin-induced focal segmental glomerulosclerosis (FSGS) model in SD rats. Further study indicated that XylA could upregulate the short-chain fatty acids (SCFAs) in vitro and vivo . Nevertheless, the relative abundance of Phascolarctobacterium in colon was increased after XylA treatment. XylA could upregulate G-protein-coupled receptor 41 (GPR41) expression, inhibit glomerular cell apoptosis and promoting proliferation. Our study expands the application of xylan and provides a new idea for the treatment of CKD with acetic acid.
研究领域:
药学
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肾脏生理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
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2025
·
IF 4.3
Fang Chen,Haiyan Wei,Dalong Liao,Yong Huang,Yijian Chen,Huiqiang Lu,Rong Xu
Colchicine is a type of alkaloid commonly used clinically for treating diseases such as gouty arthritis. Studies suggest that colchicine is toxic to the kidneys. However, the specific mechanisms are unclear. Herein, we used zebrafish to validate the renal toxicity of colchicine and investigate the underlying mechanisms. Zebrafish larvae at 3 days post-fertilization were exposed to various concentrations (15, 20, and 25 mg/L) of colchicine solution for 72 h. Results showed that colchicine caused death, slowed heart rate, slowed growth, increased interpupillary distance, caused periorbital and renal capsule edema, caused swelling of glomerular podocytes, and disrupted the development of distal convoluted tubules of renal tubules. ROS staining revealed that colchicine increased oxidative in the glomerular. Mature zebrafish adults were exposed to colchicine solution concentrations of 0.15 and 1.5 mg/L for 4 weeks. Hematoxylin eosin staining of the kidney showed that the glomerular podocyte structure was disordered, renal tubular nuclei were irregularly arranged, and cell density was reduced. A significant increase in oxidative stress kinase activity was observed. Additionally, there was abnormal expression of genes related to kidney development and function. Abnormalities in kidney injury biomarkers were also observed in zebrafish, including urea nitrogen (BUN), creatinine (CR), and β- N -acetylglucosaminidase (NAG). These findings suggest that colchicine induced developmental defects and caused renal toxicity in zebrafish. Interestingly, treatment with astaxanthin (ASTA) partially reversed the structural and physiological damage in the kidney. Conclusively, colchicine induces developmental and renal toxicity in zebrafish by upregulating oxidative stress.
研究领域:
毒理学
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发育生物学
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肾脏病学
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药理学
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氧化应激研究
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分子生物学
·
斑马鱼模型
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2020
·Vol. 11
·期 5
·1-19
·
IF 6.304
Tian Yuexin,Guo Huifang,Miao Xinyan,Xu Jie,Yang Ran,Zhao Lu,Liu Jinxi,Yang Lin,Gao Fan,Zhang Wei,Liu Qingjuan,Sun Shaoguang,Tian Yu,Li Hongbo,Huang Jie,Gu Cunyang,Liu Shuxia,Feng Xiaojuan
Podocyte injury is the main cause of proteinuria in lupus nephritis (LN). Nestin, an important cytoskeleton protein, is expressed stably in podocytes and is associated with podocyte injury. However, the role of nestin in the pathogenesis of proteinuria in LN remains unclear. The correlations among nestin, nephrin and proteinuria were analyzed in LN patients and MRL/lpr lupus-prone mice. The expression of nestin in mouse podocyte lines (MPCs) and MRL/lpr mice was knocked down to determine the role of nestin in podocyte injury. Inhibitors and RNAi method were used to explore the role of mitophagy and oxidative stress in nestin protection of podocyte from damage. There was a significantly negative correlation between nestin and proteinuria both in LN patients and MRL/lpr mice, whereas the expression of nephrin was positively correlated with nestin. Knockdown of nestin resulted in not only the decrease of nephrin, p-nephrin (Y1217) and mitophagy-associated proteins in cultured podocytes and the podocytes of MRL/lpr mice, but also mitochondrial dysfunction in podocytes stimulated with LN plasma. The expression and phosphorylation of nephrin was significantly decreased by reducing the level of mitophagy or production of reactive oxygen species (ROS) in cultured podocytes. Our findings suggested that nestin regulated the expression of nephrin through mitophagy and oxidative stress to protect the podocytes from injury in LN.
研究领域:
肾病学
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免疫学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOCONJUGATE CHEMISTRY
·
2024
·
IF 4
Yexi Peng,Yuming Qi,Mingze Xu,Yiqiao Chen,Xiaoxian Wang,Xingya Jiang,Bujie Du
Noninvasive fluorescence imaging of renal function is a valuable technique for understanding kidney disease progression and the development of renal medicine. This technique requires sensitive imaging probes for reporting renal dysfunction accurately at early stage. Herein, a molecularly engineered imaging probe (800CW–PEG45–COOH) was synthesized by simply PEGylating conventional near-infrared fluorophore IRDye800CW with NH2–PEG45–COOH (molecular weight ∼2100 Da) for early detection and staging of renal dysfunction through noninvasive real-time kidney imaging. 800CW–PEG45–COOH not only cleared through the kidney efficiently (>90% injection dosage at 24 h postinjection) but was also found to be freely filtered by glomeruli without renal tubular reabsorption and secretion. Despite this simple construction strategy, the transport of 800CW–PEG45–COOH within the kidneys was extremely sensitive to the alteration of the glomerular filtration rate (GFR), which enabled it to detect renal dysfunction much earlier than commonly used serum biomarkers and stage kidney function impairments (mild vs severe dysfunction) via imaging-based kidney clearance kinetics. This work not only provides a promising optical imaging probe for the noninvasive evaluation of kidney function but also highlights the utility of PEGylation in enhancing the performance of conventional organic dyes in biomedical applications.
研究领域:
生物医学工程
·
肾病学
·
医学成像
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-14
·
IF 16.6
Liu Di,Song Yanling,Chen Hui,You Yuchan,Zhu Luwen,Zhang Jucong,Xu Xinyi,Hu Jiahao,Huang Xiajie,Wu Xiaochuan,Xu Xiaoling,Jiang Saiping,Du Yongzhong
Poor renal distribution of antibody-based drugs is the key factor contributing to low treatment efficiency for renal diseases and side effects. Here, we prepare F(ab′) 2 fragmented vascular endothelial growth factor receptor 2 antibody (anti-VEGFR2 (F(ab′) 2 ) to block VEGFR2 overactivation in diabetic nephropathy (DN). We find that the anti-VEGFR2 F(ab′) 2 has a higher accumulation in DN male mice kidneys than the intact VEGFR2 antibody, and simultaneously preserves the binding ability to VEGFR2. Furthermore, we develop an antibody fragment drug conjugate, anti-VEGFR2 F(ab′) 2 -SS31, comprising the anti-VEGFR2 F(ab′) 2 fragment linked to the mitochondria-targeted antioxidant peptide SS31. We find that introduction of SS31 potentiates the efficacy of anti-VEGFR2 F(ab′) 2 . These findings provide proof of concept for the premise that antibody fragment drug conjugate improves renal distribution and merits drug validation in renal disease therapy.
研究领域:
药理学
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肾病学
·
糖尿病
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DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2021
·
IF 6.582
Dian Bao,Hua Su,Chun-Tao Lei,Hui Tang,Chen Ye,Wei Xiong,Fang-Fang He,Ji-Hong Lin,Hans-Peter Hammes,Chun Zhang
Rationale: Focal segmental glomerulosclerosis (FSGS) is characterized by the dysfunction of “post-mitotic” podocytes. The reentry of podocytes in the cell cycle will ultimately result in cell death. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of anaphase-promoting complex (APC)/cyclosome, precisely controls the metaphase to anaphase transition and ordered cell cycle progression. However, the role of MAD2B in FSGS podocyte injury remains unknown. Methods: To explore MAD2B function in podocyte cell cycle reentry, we used conditional mutant mice lacking MAD2B selectively in podocytes in ADR-induced FSGS murine model. Additionally, KU-55933, a specific inhibitor of ataxia-telangiectasia mutated (ATM) was utilized in vivo and in vitro to explore the role of ATM in regulating MAD2B. Results: The expression of MAD2B in podocytes was dramatically increased in patients with FSGS and ADR-treated mice along with podocyte cell cycle reentry. Podocyte-specific knockout of MAD2B effectively attenuated proteinuria, podocyte injury, and prevented the aberrant cell cycle reentry. By bioinformatics analysis we revealed that ATM kinase is a key upstream regulator of MAD2B. Furthermore, inhibition of ATM kinase abolished MAD2B-driven cell cycle reentry and alleviated podocyte impairment in FSGS murine model. In vitro studies by site-directed mutagenesis and immunoprecipitation we revealed ATM phosphorylated MAD2B and consequently hampered the ubiquitination of MAD2B in a phosphorylation-dependent manner. Conclusions: ATM kinase-MAD2B axis importantly contributes to the cell cycle reentry of podocytes, which is a novel pathogenic mechanism of FSGS, and may shed light on the development of its therapeutic approaches.
研究领域:
肾病学
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细胞生物学
·
分子生物学
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DOI
PubMed
高影响因子
Biofabrication
·
2023
·Vol. 15
·期 3
·035004
·
IF 9
Zhilin Dai,Chengpan Li,Zhengdi Shi,Shibo Li,Tianzhi Luo,Weiping Ding
Glomerulus-on-a-chip, as a promising alternative for drug nephrotoxicity evaluation, is attracting increasing attention. For glomerulus-on-a-chip, the more biomimetic the chip is, the more convincing the application of the chip is. In this study, we proposed a hollow fiber-based biomimetic glomerulus chip that can regulate filtration in response to blood pressure and hormone levels. On the chip developed here, bundles of hollow fibers were spherically twisted and embedded in designed Bowman's capsules to form spherical glomerular capillary tufts, with podocytes and endotheliocytes cultured on the outer and inner surfaces of the hollow fibers, respectively. We evaluated the morphology of cells, the viability of cells, and the metabolic function of cells in terms of glucose consumption and urea synthesis by comparing the results obtained under fluidic and static conditions, confirmed the barrier function of the endotheliocyte-fiber membrane-podocyte structure by monitoring the diffusion of fluorescein isothiocyanate (FITC)-labeled inulin, albumin and IgG, and, for the first time, achieved on-chip filtration regulation in response to the hormone atrial natriuretic peptide. In addition, the application of the chip in the evaluation of drug nephrotoxicity was also preliminarily demonstrated. This work offers insights into the design of a more physiologically similar glomerulus on a microfluidic chip.
研究领域:
生物医学工程
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组织工程
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微流控技术
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Shuhui Zhou,Liping Zheng,Tingxuan Zheng,Haiyan Zhan,Qiuyuan Lin,Jiaoao Wei,Yong Huang
Background: Nephrotic syndrome has a significant impact on global health, often leading to cardiovascular disease and high mortality due to limited effective treatments. This study investigates the efficacy of Shensu IV in a puromycin aminonucleoside (PAN)-induced rat model of nephropathy.Methods: Rat models and in vitro podocyte PAN nephropathy models were established with PAN and treated with Shensu IV. Renal function was evaluated by measuring urine output and protein content, while hydrogen sulfide (H2S) and oxidative stress markers were quantified in serum and podocyte lysates. We conducted histological examination on kidney tissues and analyzed molecular markers (CD2AP, nephrin, and PI3K/AKT pathway) using RT-qPCR and Western blot.Results: Shensu IV significantly improved urine output and proteinuria, and attenuated glomerular damage, fibrosis, and mitochondrial swelling in PAN-treated rats. Mechanistically, Shensu IV enhanced endogenous H2S production, reducing oxidative stress and activating the PI3K/AKT pathway in vivo and in vitro. This facilitated the upregulation of the target genes CD2AP and nephrin, which are critical for maintaining glomerular integrity and improving renal function in PAN nephropathy models.Conclusion: Shensu IV and NaHS confer renal protection primarily by modulating oxidative stress and restoring the integrity of the glomerular filtration barrier through mechanisms involving the enhancement of the PI3K/AKT pathway and modulation of H2S levels. These findings suggest a promising therapeutic potential for these metabolites in the treatment of nephrotic syndrome.
研究领域:
药理学
·
肾病学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）