Frontiers in Medicine
·
2024
·
IF 3.1
Liu Yan,Ge Ri-Li,Shan Zhen-Zhen,Wang Yan-Jun,Yang Yan-Yan,Sun Xue,Luo Peng-Li
Podocytopathies encompass kidney diseases where direct or indirect podocyte injury leads to proteinuria or nephrotic syndrome. Although Semaphorin3A (Sema3A) is expressed in podocytes and tubular cells in adult mammalian kidneys and has a common effect on the progression of podocyte injury, its mechanism remains unclear. Previous studies have shown increased Sema3A expression in various glomerulopathies, indicating a gap in understanding its role. In this study, analysis of human data revealed a positive correlation between the levels of urinary Sema3A and Podocalyxin (PCX), suggesting a close relationship between Sema3A and podocyte loss. Furthermore, the impact of Adriamycin on podocytes was investigated. Adriamycin induced podocyte migration and apoptosis, along with an increase in Sema3A expression, all of which were ameliorated by the inhibition of Sema3A. Importantly, TRPC5 was found to increase the overexpression of Sema3A in podocytes. A TRPC5 inhibitor, AC1903, alleviated podocyte migration and apoptosis, inhibiting the formation of lamellar pseudopodia in the podocyte cytoskeleton by lowering the expression of Rac1. Furthermore, AC1903 relieved massive albuminuria and foot process effacement in the kidneys of Adriamycin-treated mice in vivo. In conclusion, our findings suggest that Sema3A may impact the cytoskeletal stability of podocytes through TRPC5 ion channels, mediated by Rac1, ultimately leading to foot process effacement. Notably, AC1903 demonstrates the potential to reverse Adriamycin-induced foot process fusion and urine protein. These results contribute to a deeper understanding of the mechanisms involved in podocytopathies and highlight the therapeutic potential of targeting the Sema3A-TRPC5 pathway.
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
International Journal of Biological Sciences
·
2021
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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
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分子生物学
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DOI
PubMed
高影响因子
Pharmaceuticals
·
2024
·Vol. 17
·期 11
·1416
·
IF 4.3
Ziang Zhou,Yumeng Wang,Yu Xing,Shuman Pan,Wanru Wang,Jie Yang,Wenyuan Wu,Jie Zhou,Luyi Huang,Qiongdan Liang,Dongmei Zhang,Lingdong Kong
Background/Objectives: High fructose has been implicated as an important trigger of kidney inflammation in patients and experimental models. Magnolol, isolated fromMagnolia officinalis, has an anti-inflammatory effect, but its protective role in podocytes remains underexplored. This study explored the protective effects and underlying mechanism of magnolol against high fructose-induced podocyte inflammation. Methods: The effects of magnolol on high fructose-induced podocyte inflammation were assessed in male Sprague Dawley rats administered 10% (w/v) fructose water for 12 weeks and heat-sensitive human podocyte cell lines (HPCs) exposed to 5 mM fructose. Podocyte foot processes were examined using transmission electron microscopy. The expression levels of nephrin, podocin, tumor necrosis factor-α (TNF-α), Notch1 intracellular domain (NICD1), triokinase/FMN cyclase (TKFC), specificity protein 1 (Sp1) and histone deacetylase 4 (HDAC4) were determined by Western blot, immunofluorescence and real-time quantitative polymerase chain reaction (qRT-PCR). The chromatin immunoprecipitation (ChIP) assay was performed to evaluate the interaction between Sp1 and the promoter region of HDAC4. Results: Magnolol mitigated the impairment of glomerular filtration function in high fructose-fed rats. Besides, it significantly alleviated the inflammatory responses in glomeruli and HPCs, evidenced by decreased protein levels of TNF-α and NICD1. Increased protein levels of TKFC, Sp1 and HDAC4 were observed in high fructose-stimulated HPCs and rat glomeruli. TMP195, an HDAC4 inhibitor, reduced TNF-α and NICD1 protein levels in high fructose-exposed HPCs. The increased Sp1 was shown to associate with the promoter region of HDAC4, promoting HDAC4 protein expression in high fructose-exposed HPCs. The knockdown of TKFC in HPCs byTKFCsiRNA decreased Sp1, HDAC4 and NICD1 protein levels, alleviating podocyte inflammatory response. Furthermore, magnolol inhibited TKFC/Sp1/HDAC4/Notch1 activation in vivo and in vitro. Conclusions: Magnolol attenuated high fructose-induced podocyte inflammation possibly through the suppression of TKFC/Sp1/HDAC4/Notch1 activation, providing new evidence for its potential role in podocyte protection.
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
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
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2025
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IF 2.8
Aiping Li,Xiaoyu Zhang,Zheng Ju,Tingting Luo,Ting Cui,Xuemei Qin,Guangzhen Liu
To elucidate the molecular mechanisms of the MIX (combined in proportion to the content in Astragali Radix (AR), named the MIX) repairing podocyte damage to ameliorate nephropathy. MTT assay and western blot analysis were used to evaluate the protective effects of MIX on MPC5 cells induced by Adriamycin (ADR). Screening of potential pharmacodynamic markers, relevant drugs and disease targets were conducted by using metabolomics combined with bioinformatics, and the most relevant metabolic pathways were identified by analyzing shared target and KEGG pathways. The key mechanism was subsequently validated by cell adhesion assays, western blot assays, and immunofluorescence staining. The results showed that the MIX has the capacity to repair adriamycin-induced damage in MPC5 cells, as evidenced by enhanced cell viability and synaptopodin expression. Additionally, the MIX shows promise in potentially reinstating the podocyte adhesion through the modulation of the expression of podocyte adhesion-related proteins linked to nucleotide metabolites. The MIX has the potential to beneficially affect podocyte injury by modulating the cell adhesion pathway, contributing to one of the pharmacodynamic mechanisms of AR treatment of nephrotic syndrome. This has implications for the development and utilization of AR resources and achievement the social benefit of empowering rural revitalization.
研究领域:
药理学
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代谢组学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
International Journal of Endocrinology
·
2025
·Vol. 2025
·期 1
·4473803
·
IF 2.3
Song Xue,Wei Fan,Qingping Li,Hong Huang,Yibo Tang,Min Wu
Background: This study aimed to investigate the potential mechanisms of puerarin in alleviating diabetic nephropathy (DKD) in mice. Method: The DKD model was induced by multiple low-dose injections of streptozotocin (STZ) and a high-sugar and high-fat diet in male C57BL/6J mice. After confirming the onset of DKD, mice were given irbesartan, distilled water, or different concentrations of puerarin (40 and 80 mg/kg/d) by gavage for 8 weeks. HE staining and PAS staining were adopted to assess the pathological changes in the kidney tissues. Meanwhile, the levels of superoxide dismutase, catalase, creatinine, and cystatin C in the serum and the urine albumin and creatinine were measured, and the renal indices as well as the urinary albumin-to-creatinine ratio (UACR) were calculated. The changes of podocin and protein expression levels associated with AMPK/Nrf2 signaling pathway were evaluated by western blot. Results: Puerarin significantly reduced the level of fasting blood glucose, renal index, glomerular mesangial expansion index, renal function, and oxidative stress induced by STZ ( p < 0.05). The pathological injuries in kidney tissues were also alleviated. Furthermore, we demonstrated that the expression level of podocin and protein related to the AMPK/Nrf2 signaling pathway was also decreased significantly by the treatment of puerarin. At the same time, the efficacy of puerarin in the treatment of DKD was better than that of irbesartan, and the treatment effect of the high-dose group (80 mg/kg/d) was also significantly better than that of the low-dose group (40 mg/kg/d). Conclusion: Puerarin could attenuate the severity of DKD and protect the podocyte in mice in a dose-dependent way. Also, it might be performed by regulating the AMPK/Nrf2 pathway. These findings may provide a theoretical basis for updating the clinical management of DKD.
研究领域:
医学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2023
·Vol. 21
·期 1
·1-17
·
IF 10.2
Liu Lili,Chang Meiqi,Yang Rong,Ding Li,Chen Yu,Kang Yulin
Background Primary nephrotic syndrome (PNS) is characterized by edema, heavy proteinuria, hypoalbuminemia and hyperlipidemia. Moreover, podocyte injury is the key pathological change of PNS. Even though the pathophysiological etiology of PNS has not been fully understood, the production of excessive reactive oxygen species (ROS) plays an important role in the development and progression of the disease. Glucocorticoids are the first-line medications for patients with PNS, but their clinical use is hampered by dose-dependent side effects. Herein, we accelerated the rate of conversion from Ce 4+ to Ce 3+ by doping Zr 4+ in ceria-zirconia nanomedicines to treat the PNS rat model by removal of ROS. Results The engineered Ce 0.7 Zr 0.3 O 2 (7CZ) nanomedicines significantly improved the ROS scavenging ability of podocytes at a very low dose, enabling effective inhibition of podocyte apoptosis and actin cytoskeleton depolymerization induced by adriamycin (ADR). Accordingly, podocyte injury was effectively alleviated in rat models of ADR-induced nephrotic syndrome, as confirmed by serum tests and renal tissue staining. Moreover, the mRNA sequencing assay revealed the protective molecular signaling pathways of 7CZ nanomedicines in podocytes. Conclusion 7CZ nanomedicines were highly effective in protecting against ADR-induced podocyte injury in vitro and in vivo at a very low concentration. Graphical Abstract
研究领域:
纳米医学
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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
EXPERIMENTAL CELL RESEARCH
·
2024
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IF 3.3
Yanhua Jin,Huan Wang,Yu Xin,Yanning Zhang
Mitochondrial dysfunction is a pivotal factor in the onset of podocyte damage, which is a central component in the pathogenesis of nephrotic syndrome (NS). However, the precise mechanisms underlying the changes in podocyte mitochondria remain elusive. Our study aims to clarify the potential mechanisms involved in the role of F-box protein 11 (Fbxo11) in NS, specifically concentrating on its impact on mitochondrial function. A mouse model was established by tail vein injection of adriamycin (ADR, 10 mg/kg) and was infected with lentivirus overexpressing Fbxo11. Mouse podocytes (MPC-5) were infected with lenti-Fbxo11-OE, followed by treatment with 0.4 μg/mL of ADR. We identified the decreased expression of Fbxo11 in mouse kidney tissues and MPC-5 cells induced by ADR. Lenti-Fbxo11-OE intervention relieved ADR-induced glomerular lesion, podocyte injury, and mitochondrial dysfunction. In vitro, overexpression of Fbxo11 in mouse podocytes improved mitochondrial function and reduced podocyte damage, thereby inhibiting podocyte apoptosis. Mechanistically, Fbxo11 decreased the protein expression of Fosl2 through ubiquitin-dependent proteasomal degradation. Rescue experiments revealed that overexpression of Fosl2 abolished the protective effects of Fbxo11 overexpression on mitochondrial damage and podocyte injury. Importantly, the regulatory effects of the Fbxo11/Fosl2 axis were reversed when treated with the mitochondrial fission inhibitor mdivi-1. Taken together, our results demonstrated that Fbxo11-mediated ubiquitin degradation of Fosl2 is critical for maintaining mitochondrial function and preventing podocyte injury during NS.
研究领域:
肾病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
·
IF 5.4
Lei Yan,Qin Zeng,Wenru Wang,Ying Liang,Rui Lang,Jingyi Zhan,Jiayi Yang,Renhuan Yu,Xinhui Wang
Ethnopharmacological relevance Jianpi Qushi Heluo formula (JQHF) is an evidence-based herbal formula based on "Fangji Huangqi Decoction" in the classic of traditional Chinese medicine (TCM) synopsis of the Golden Chamber. Its effectiveness in reducing idiopathic membranous nephropathy (IMN) proteinuria, edema and other clinical symptoms and improving kidney injury has been confirmed by clinical trials and animal experiments. These results demonstrate the critical significance of reducing podocyte injury by regulating mitophagy through integrating ethnopharmacology. Aim of the study This study aimed to explore the protective effects of JQHF on podocyte injury in IMN, focusing on its role in promoting PINK1-dependent mitophagy to inhibit reactive oxygen species (ROS) mediated activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Materials and Methods The main components of JQHF were identified by ultra-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MSE). Passive Heymann nephritis (PHN) was induced in rats using anti-Fx1A antiserum, while podocyte injury in vitro was stimulated with sublytic complement C5b-9 (sC5b-9). The PHN rats were treated with JQHF, and autophagy inhibitor 3-methyladenine (3-MA) combined with JQHF was used for pathway verification, and Benazepril served as a positive control. In vitro, podocytes were exposed to palmitic acid (PA, a ROS inducer) and N-acetylcysteine (NAC, a ROS scavenger). Further, we silenced the expression of PINK1 in podocytes model and intervened with JQHF-containing serum. Renal function was assessed through biochemical analyses and histopathology. Mitochondrial function was measured by detecting mitochondrial membrane potential (MMP), ROS levels as well as mitochondrial ultrastructure. The expression of podocyte structural proteins (desmin, nephrin, podocin) and inflammasome-related markers (NLRP3, caspase-1, IL-1β, IL-6) was analyzed to assess podocyte injury and inflammasome activation. Results (1) In vitro, in contrast to the control group, PA intervention caused increased ROS accumulation, reduced MMP, upregulated NLRP3 and caspase-1 expression, as well as elevated expression of inflammatory factors IL-1β and IL-6. The expression of nephrin and podocin was notably reduced. By contrast, NAC reversed these effects. (2) In vivo, JQHF effectively ameliorated mitochondrial damage, reduced NLRP3 expression and mitigated podocyte injury in PHN rats. The protective effects of JQHF were diminished by 3-MA, confirming the involvement of autophagy. (3) In vitro, JQHF-containing serum attenuated C5b-9-induced podocyte injury, improved mitochondrial dysfunction, and inhibited ROS-mediated activation of NLRP3 inflammasome. Silencing PINK1 significantly reversed these protective effects. Conclusion JQHF can alleviate podocyte damage, that through inhibiting ROS-mediated NLRP3 inflammasome activation by improving PINK1-mediated mitophagy.
研究领域:
免疫学
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分子生物学
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药理学
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转化医学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
PeerJ
·
2023
·
IF 2.7
Linlin Sun,Miao Ding,Fuhua Chen,Dingyu Zhu,Xinmiao Xie
Podocyte injury is a critical factor in the pathogenesis of diabeticnephropathy (DN). Emerging evidence has demonstrated that breviscapine (Bre) exerts a renoprotective effect on diabetic rats. However, the effects of Bre on regulating podocyte injury under high glucose (HG) conditions remain unclear. In this study, an experimental mouse model of DN was induced by intraperitoneal injections of streptozotocin (STZ) in vivo . The effects of Bre on podocyte injury were assessed using cell counting kit-8 (CCK-8) assay, TdT-mediated dUTPnick-endlabelling (TUNEL) staining, quantitative real-time PCR (qRT‒PCR) and western blot analysis. We found that renal function was significantly decreased in diabetic mice, and this effect was blocked by Bre treatment. Bre effectively increased podocyte viability and inhibited HG-induced cell apoptosis. Furthermore, Bre ameliorated HG-induced podocyte injury, as evidenced by decreased α-smooth muscle actin (α-SMA) expression and increased podocin and synaptopodin expression. Mechanistically, Bre inhibited HG-induced nuclear factorkappaB (NF-κB) signalling activation and subsequently decreased NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, resulting in a decrease in pyroptosis. Pharmacological inhibition of NLRP3 decreased HG-induced podocyte injury, whereas the NLRP3 agonist abrogated the effects of Bre on inhibiting podocyte injury. In summary, these results demonstrate that Bre alleviates HG-induced podocyte injury and improves renal function in diabetic mice, at least in part by inhibiting NF-κB/NLRP3-mediated pyroptosis.
研究领域:
药理学
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肾病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR THERAPY
·
2023
·
IF 12.4
Yang Qiu,Chuntao Lei,Jieyu Zeng,Yaru Xie,Yiling Cao,Qian Yuan,Hua Su,Zhentao Zhang,Chun Zhang
Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disorder causing end-stage renal diseases worldwide. Central to the pathogenesis of FSGS is podocyte dysfunction, which is induced by diverse insults. However, the mechanism governing podocyte injury and repair remains largely unexplored. Asparagine endopeptidase (AEP), a lysosomal protease, regulates substrates by residue-specific cleavage or degradation. We identified the increased AEP expression in the primary proteinuria model which was induced by adriamycin (ADR) to mimic human FSGS. In vivo , global AEP knockout mice manifested increased injury-susceptibility of podocytes in ADR-induced nephropathy (ADRN). Podocyte-specific AEP knockout mice exhibited much more severe glomerular lesions and podocyte injury after ADR injection. In contrast, podocyte-specific augmentation of AEP in mice protected against ADRN. In vitro , knockdown and overexpression of AEP in human podocytes revealed the cytoprotection of AEP as a cytoskeleton regulator. Furthermore, transgelin, an actin-binding protein regulating actin dynamics, was cleaved by AEP, and, as a result, removed its actin-binding regulatory domain. The truncated transgelin regulated podocyte actin dynamics and repressed podocyte hypermotility, compared to the native full-length transgelin. Together, our data reveal a link between lysosomal protease AEP and podocyte cytoskeletal homeostasis, which suggests a potential therapeutic role for AEP in proteinuria disease.
研究领域:
分子生物学
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肾脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
·
2025
·Vol. 39
·期 9
·e70455
·
IF 2.8
Lihan Xie,Weinan Li,Shiqi Fan,Jinsong Jin
Diabetic kidney disease (DKD) is a common complication of diabetes, often characterized by podocyte injury, proteinuria, and eventual renal failure. Sinomenine hydrochloride (SH), an active component derived from traditional Chinese medicine, is clinically effective in treating kidney diseases. This study investigates the protective effects of SH on podocytes under high-glucose conditions and its mechanism of action. Mouse podocytes (MPC-5) were treated with SH at concentrations of 50, 200, and 600 μg/mL under high-glucose conditions (30 mmol/L) for 24 h to establish a DKD model. Cell viability was assessed using CCK-8 assays, and apoptosis rates were measured using flow cytometry. Autophagy levels were evaluated by detecting LC3-II, Beclin-1, and P62 proteins via Western blot analysis, while the involvement of the PI3K/AKT/mTOR pathway was analyzed by examining phosphorylated AKT and mTOR. Transmission electron microscopy was employed to observe autophagosomes. SH improved podocyte viability, reduced apoptosis, and enhanced autophagic activity by increasing LC3-II and Beclin-1 expression while decreasing P62 levels. SH also downregulated p-AKT and p-mTOR, indicating inhibition of the PI3K/AKT/mTOR pathway. Electron microscopy confirmed increased autophagosomes in SH-treated groups. SH protects podocytes in a high-glucose environment by enhancing autophagy through inhibition of the PI3K/AKT/mTOR pathway. These findings provide insights into SH as a potential therapeutic agent for DKD management.
研究领域:
药理学
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细胞生物学
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肾病学
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分子生物学
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中医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RENAL FAILURE
·
2023
·
IF 3
Chenlei Lv,Tianyang Cheng,Bingbing Zhang,Ke Sun,Keda Lu
Objectives: Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus. This study investigated the mechanism of triptolide (TP) in podocyte injury in DN.Methods: DN mouse models were established by feeding with a high-fat diet and injecting with streptozocin and MPC5 podocyte injury models were induced by high-glucose (HG), followed by TP treatment. Fasting blood glucose and renal function indicators, such as 24 h urine albumin (UAlb), serum creatinine (SCr), blood urea nitrogen (BUN), and kidney/body weight ratio of mice were examined. H&E and TUNEL staining were performed for evaluating pathological changes and apoptosis in renal tissue. The podocyte markers, reactive oxygen species (ROS), oxidative stress (OS), serum inflammatory cytokines, nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway-related proteins, and pyroptosis were detected by Western blotting and corresponding kits. MPC5 cell viability and pyroptosis were evaluated by MTT and Hoechst 33342/PI double-fluorescence staining. Nrf2 inhibitor ML385 was used to verify the regulation of TP on Nrf2.Results: TP improved renal function and histopathological injury of DN mice, alleviated podocytes injury, reduced OS and ROS by activating the Nrf2/heme oxygenase-1 (HO-1) pathway, and weakened pyroptosis by inhibiting the nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome pathway. In vitro experiments further verified the inhibition of TP on OS and pyroptosis by mediating the Nrf2/HO-1 and NLRP3 inflammasome pathways. Inhibition of Nrf2 reversed the protective effect of TP on MPC5 cells.Conclusions: Overall, TP alleviated podocyte injury in DN by inhibiting OS and pyroptosis via Nrf2/ROS/NLRP3 axis.
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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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
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