RENAL FAILURE
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2025
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IF 3
Ningjun Shao,Kedan Cai,Yue Hong,Lingping Wu,Qun Luo
Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates many critical genes associated with iron storage and transportation, the activity of which is influenced by E3 ligase-mediated ubiquitination. We wondered whether there is a deubiquitinase that mediates the deubiquitination of Nrf2 to stabilize Nrf2 expression and further prevent diabetic kidney disease (DKD). High glucose (HG) was applied to induce an in vitro model of DKD. The effects of HG on HK-2 cell viability, apoptosis, Fe2+ level, Nrf2, and ubiquitin-specific protease 9X (USP9X) were assessed by cell counting kit-8 (CCK-8) assay, flow cytometry, iron assay, and Western blot. The direct interaction between Nrf2 and USP9X was analyzed using co-immunoprecipitation and ubiquitination assay. After transfection and ferrostatin-1 (Fer-1) intervention, Nrf2 and USP9X levels, cell viability, apoptosis, and Fe2+ level were tested again. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) contents, and ferroptosis-related markers were assessed by ROS assay kit, ELISA, and Western blot. HG reduced cell viability and levels of USP9X and Nrf2, while elevating apoptosis and Fe2+ level. An interaction between USP9X and Nrf2 has been verified and USP9X deubiquitinated Nrf2. Nrf2 up-regulation augmented the viability, GSH content, and ferroptosis-related protein expressions, while suppressing the apoptosis, Fe2+ level, MDA, and ROS content in HG-mediated HK-2 cells, which was reversed by USP9X silencing. Fer-1 offset the combined modulation of Nrf2 and siUSP9X on HG-induced HK-2 cells. USP9X mediates Nrf2 deubiquitinase to hamper the ferroptosis in DKD in vitro.
研究领域:
分子生物学
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肾脏病学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Jing Zhang,Xuewei Yang,Xing Zhao,Gang Luo,Hong Jiang
Renal fibrosis is recognized as a critical pathway leading to end-stage renal disease in nearly all cases of chronic kidney disease (CKD). Analysis of the gene expression omnibus (GEO) database revealed that the transcription factor Krüppel-like factor 3 (KLF3) was elevated in kidney tissues of CKD patients, however, its specific role in CKD-associated renal fibrosis is yet to be deciphered. This study aimed to investigate the function of KLF3 on unilateral ureteral obstruction (UUO) mice and transforming growth factor-β1 (TGF-β1)-stimulated HK2 cells. Our data demonstrated that KLF3 was remarkably upregulated in the renal cortex of UUO mice and TGF-β1-treated HK-2 cells. We further confirmed that the upregulation of KLF3 was associated with its N6-methyladenosine (m6A) methylation modification. Knockdown of METTL14 reduced m6A methylation level of KLF3 and inhibited its mRNA stability. In vivo results suggested that KLF3 knockdown alleviated the pathological changes in renal tissues triggered by UUO. Additionally, KLF3 silencing mitigated renal fibrosis both in vivo and in vitro , as accompanied by decreased expression of Collagen I, Vimentin, α-SMA and Fibronectin. Mechanistically, KLF3 transcription activated dimethylarginine dimethylaminohydroxylase 2 (DDAH2) and upregulated its expression. Rescue experiments substantiated that DDAH2 overexpression eliminated the effect of KLF3 knockdown on renal fibrosis. Collectively, our findings suggest that inhibition of KLF3 may serve as a potential strategy to prevent CKD-associated renal fibrosis.
研究领域:
分子生物学
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肾脏病学
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DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2024
·Vol. 38
·期 6
·e5866
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IF 1.8
Zhijian Zha,Ruihua Wang,Qian Wang,Fahui Chen,Ziyang Ye,Yafeng Li
Immunoglobulin nephropathy (IgAN) stands as the most prevalent primary glomerular nephropathy globally, typically diagnosed through an invasive renal biopsy. Emerging research suggests the significant involvement of chiral amino acids in kidney disease progression. This study introduces a nonderivative LC–tandem mass spectrometry approach, offering efficient separation outcomes within 15 min for identifying chiral amino acids in human urine samples. Subsequently, using this method, the analysis of l - and d -amino acids in the urine of both patients with IgAN and healthy individuals was conducted. Fourteen d -amino acids and 20 l -amino acids were identified in the urine samples obtained from 17 patients with IgAN and 21 healthy individuals. The results indicated notable variances in the concentrations of both l - and d -amino acids between the IgAN and healthy control groups. In contrast to the healthy group, the IgAN group exhibited higher mean urine concentrations of most l -amino acids and lower concentrations of d -amino acids. Furthermore, correlations between amino acids and clinical markers were investigated. These results propose a novel method for monitoring trace amino acids in urine samples and introduce a new concept for potential markers of IgAN.
研究领域:
医学
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分析化学
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肾脏病学
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DOI
PubMed
高影响因子
Journal of Physiological Investigation
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2024
·Vol. 67
·期 2
·69
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IF 0
Wang Chunli,Xu Mingzhi,Bai Yafei,Pan Mingjiao,Qi Yonghui,Chen Ruman
Vascular calcification (VC), a major complication in chronic kidney disease (CKD), is predominantly driven by osteoblastic differentiation. Recent studies have highlighted the crucial role of microRNAs in CKD’s pathogenesis. Here, our research focused on the effects of miR-204-5p and its molecular mechanisms within VC. We initially found a notable decrease in miR-204-5p levels in human aortic vascular smooth muscle cells stimulated with inorganic phosphate, using this as a VC model in vitro. Following the overexpression of miR-204-5p, a decrease in VC was observed, as indicated by alizarin red S staining and measurements of calcium content. This decrease was accompanied by lower levels of the osteogenic marker, runt-related transcription factor 2, and higher levels of α-smooth muscle actin, a marker of contractility. Further investigation showed that calcium/calmodulin-dependent protein kinase 1 (CAMK1), which is a predicted target of miR-204-5p, promotes VC. Conversely, overexpressing miR-204-5p reduced VC by suppressing CAMK1 activity. Overexpressing miR-204-5p also effectively mitigated aortic calcification in an in vivo rat model. In summary, our research indicated that targeting the miR-204-5p/CAMK1 pathway could be a viable strategy for mitigating VC in CKD patients.
研究领域:
分子生物学
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病理学
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心血管科学
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遗传学
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DOI
Cell Communication and Signaling
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2025
·Vol. 23
·期 1
·1-21
·
IF 8.9
He Qiongyao,He Wu,Ren Yanlin,Wu Wenbin,Dong Hui,Yuan Gang,Ren Huihui,Wang Xinwei,Lu Fuer,Wang Dingkun
Ferroptosis, an iron-dependent form of programmed cell death, is closely associated with tubular damage in diabetic nephropathy (DN). Glutathione peroxidase 4 (GPX4) is an important anti-oxidant enzyme, and plays a crucial role in protecting against ferroptosis. However, the regulatory mechanism of GPX4 expression levels in renal tubular epithelial cells (RTECs) remains elusive. This study reveals that ferroptosis occurs in the late-stage of DN, and the GPX4 level is significantly downregulated in DN patients, animal models and cell models. By applying database predictions, luciferase reporter assays and chromatin immunoprecipitation, we find that vitamin D receptor (VDR) transcription factor promotes GPX4 expression and plays a key role in inhibiting ferroptosis of RTECs. VDR knockout exacerbates ferroptosis in RTECs and worsens renal function, while intraperitoneal injection of VDR agonist paricalcitol significantly improves renal injury. Proteomics analysis suggests that E3 ligase PRPF19 mediates ubiquitination degradation of VDR and is an important therapeutic target for DN. Therefore, through molecular docking, targeted fishing technology using high-performance affinity beads, and surface plasmon resonance (SPR), we screen and identify berberine (BBR) as a novel inhibitor of PRPF19, which offers renal protection by inhibiting VDR degradation and tubular ferroptosis. These findings elucidate the role of ferroptosis in DN renal tubular injury, and suggest that PRPF19 is a promising therapeutic target.
研究领域:
医学
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分子生物学
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肾脏病学
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PubMed
高影响因子
Journal of Proteomics
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2024
·
IF 2.8
Yan Cai,Weifu Ren,Siqian Li,Rijing Liao,Qi Bian
Idiopathic membranous nephropathy (IMN) is an antibody-mediated and kidney-specific autoimmune disease, with the antigen phospholipase A2 receptor 1 (PLA2R1) accounting for approximately 70% of IMN cases. Although a variety of new podocyte target antigens and their autoantibodies have been identified, they are still of limited diagnostic and therapeutic value due to lack of high specificity and sensitivity. N-glycans play vital roles in renal system and their pathobiological relevance has become increasingly recognized in many kidney diseases, but not fully explored in IMN. To find possible glyco-signatures for PLA2R1-related IMN diagnosis, we herein established a comprehensive workflow for total serum N-glycome analysis based on our recently developed mass spectrometry (MS)-based N-glycan purification method, named Ultrafast Glycoprotein Immobilization for Glycan extraction (UltraGIG). A total of 191 N-glycans were identified from IMN patients, representing the largest N-glycome dataset in IMN. Compared to healthy controls, up-regulation of sialylation and core-fucosylation as well as down-regulation of galactosylation were observed in PLA2R1-positive IMN patients, and up-regulation of hyper-galactosylation was specific for PLA2R1-negative IMN patients. A six-glycan marker panel consisting of H4N3S1, H4N3F1, H6N4S2, H6H5F1S2, H6N5 and H6N6F1S1, was proposed to aid in the accurate diagnosis of PLA2R1-related IMN, which provided new insights into IMN biomarker study . Significance PLA2R1-related IMN is a kidney-specific autoimmune disease with a high risk of developing end-stage renal disease (ESRD) and even kidney failure. Current biomarkers are still of limited diagnostic and therapeutic value due to lack of high specificity and sensitivity. An in-depth MS analysis of total serum N-glycome of PLA2R1-related IMN patients was conducted for the first time. We generated the largest dataset of serum N-glycome for IMN to date, and proposed a novel six-glycan marker panel that may help the accurate diagnosis of PLA2R1-related IMN.
研究领域:
医学
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肾脏病学
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蛋白质组学
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免疫学
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PubMed
高影响因子
JOURNAL OF LIPOSOME RESEARCH
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2025
·
IF 4.3
Qinyang Hua,Qilong Wang,Xue Wang,Xia Jiang,Mingjie Gong,Jiaying Li,Tingyuan Li,Xiaowen Wang,Xia Cao,Jiangnan Yu,Elmurat Toreniyazov,Bin Zong,Ximing Xu,Feng Shi,Michael Adu-Frimpong
The clinical application of Isoquercitrin (IQ) is limited by its low water solubility and short retention time in the body, despite its diverse pharmacological effects. To address these issues, we prepared polyethylene glycol (PEG)-modified IQ liposomes (IQ-L) using the thin film dispersion method and optimized the formulation through a combination of One Factor at a Time (OFAT) method and response surface experiments. Characterization of the IQ-L that was prepared using the optimal formulation revealed a particle size of 185.48 nm, a polydispersity index of 0.252, a zeta potential of −33.88 mV, and an impressive encapsulation efficiency of 97.84%. In vitro release studies showed a significantly higher cumulative release rate for IQ-L compared to free IQ. Pharmacokinetic evaluations in rats demonstrated a 4.54-fold increase in the area under the concentration-time curve, a 1.63-fold prolongation of the half-life, and a 2.07-fold increase in peak concentration for IQ-L compared to unmodified IQ. Moreover, assessments of renal function in a mouse model indicated promising therapeutic effects. In summary, the PEG-modified liposome system greatly improved the solubility and in vivo retention time of IQ, thus making it a potential clinical agent for the treatment of chronic kidney disease (CKD).
研究领域:
药剂学
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肾脏病学
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生物医学工程
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DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
·
2022
·
IF 6.911
Yan Cai,Weifu Ren,Haiyan Wang,Qi Bian
Diabetic kidney disease (DKD) is a common and serious kidney-related complication of diabetic mellitus. Although albuminuria and estimated glomerular filtration rate (eGFR) are commonly used diagnostic biomarkers, they have limitations in the diagnosis of DKD due to the lack of specificity and sensitivity. Urinary N-glycans are emerging as novel biomarkers for predicting renal prognosis in DKD. However, most of the current N-glycan profiling methods for DKD were based on lectin affinity enrichment or hydrophilic interaction chromatography (HILIC) with optical detection, which provided limited N-glycome coverage in low throughput. Herein, we developed a novel N-glycan purification method, termed Ultrafast Glycoprotein Immobilization for Glycan extraction (UltraGIG), for in-depth profiling of urinary N-glycome in DKD using mass spectrometry (MS). In UltraGIG, proteins were rapidly (within 40 min) immobilized to resin with high efficiency (over 98%) through NHS-reactive chemistry , and then N-glycans were enzymatically released from the resin by PNGase F. Owing to good efficiency of immobilization of proteins to resin, the subsequent washing steps to remove proteins and other impurities could be easily performed. The UltraGIG showed good selectivity towards glycans (extracting N-glycans from the mixture of IgG and BSA at a 1:100 M ratio) and samples loss was minimized (detection sensitivity at fmol level). A total of 237 N-glycan compositions were identified from urine samples with DKD and healthy controls, which representing the largest data set of N-glycome from DKD. Compared to healthy controls, 3 N-glycans were up-regulated and 14 N-glycans were down-regulated in DKD patients. Collectively, UltraGIG offers a competitive sample purification method for in-depth analysis of urinary N-glycome by MS and provide new insights into biomarker study for the diagnosis of DKD.
研究领域:
医学
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生物化学
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DOI
PubMed
高影响因子
BMC Nephrology
·
2025
·Vol. 26
·期 1
·1-14
·
IF 2.4
Wang Yu,Zhang Jingjing,Tang Qian
Background Diabetic nephropathy (DN) is a primary contributor to end-stage renal disease, yet the underlying molecular mechanisms remain incompletely understood. This study aims to elucidate the role of RNA-binding proteins (RBPs) and RBP-alternative splicing (AS) regulatory networks in the pathogenesis of DN. Methods Two RNA-seq datasets (GSE117085 and GSE142025) were retrieved from the Sequence Read Archive (SRA) database. Regulated alternative splicing events (RASEs) and genes (RASGs) of RASEs, along with differentiated RBPs, were identified. Validated differentiated RBPs were correlated with clinical features using the Nephroseq v5 online platform. Using the DN mouse model and RT-qPCR, validated the alternative splicing of RNA. Results Our analysis revealed 15 differentiated RBP genes and 423 RASEs in the kidney cortex of DN rats compared to controls. Enrichment analysis highlighted lipid metabolism pathways for RASGs. Seven of the identified RBPs were validated in kidney biopsy samples from DN patients versus controls. A co-deregulatory network was constructed based on dysregulated RBPs and RASEs, with select RASGs identified. In vivo experiments, compared to normal mice, the mRNA levels of RPS19 were significantly elevated in the renal tissues of DN mice, while the levels of CPEB4 and CRYZ were markedly decreased. Conclusion In conclusion, this study provides evidence implicating dysregulated RBPs and RBP-AS regulatory networks in the development of diabetic nephropathy. The validated RBPs exhibited close associations with clinical biomarkers, reinforcing their potential as therapeutic targets for DN. These findings enhance our understanding of the molecular basis of DN and offer new insights for future research and intervention strategies. Clinical trial Not applicable.
研究领域:
分子生物学
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基因组学
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肾脏病学
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生物信息学
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发病机制
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DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
·
2025
·
IF 6
Haijing Tian,Ruo Wu,Qi Lv,Jie Shi,Xiaoqin Guo,Duo Li,Chunli Liu,Qi Li,Weijia Zheng,Haojun Fan,Xuexin Duan,Qiannan Xue
Blood potassium and creatinine levels are critical indicators for managing chronic kidney disease (CKD). In response to the need for home monitoring and emergency care, point-of-care diagnostic technologies based on microsystems have emerged, nevertheless they remain limited in portability and speed for direct in whole blood samples measurement. To enable direct blood detection of potassium and creatinine for effective CKD management, this study presents a novel on-chip self-driven dual-channel optical microsensor designed for real-time monitoring of potassium and creatinine levels in whole blood. Utilizing 3D printing technology to design and fabricate microstructures, and integrating microchannels with a filtration layer, this microsensor requires only 10 μL of blood for single-pass sample filtration and dual-parameter detection. A novel passive blood sample pumping method is proposed, utilizing internal and external pressure differentials along with internal hydrophilic properties to facilitate sample flow into the detection chambers. Light-emitting diodes (LEDs) and photodiodes, positioned on either side of the detection chamber, are employed to measure the concentrations of blood indicators. The detection results can be instantly handheld read and uploaded to the cloud via intelligent terminal, enabling seamless follow-up diagnostics and treatment. Through multiple rounds of testing on animal serum samples, whole blood samples, and real porcine blood samples, this microsensor demonstrated excellent linearity and accuracy. This innovative microsensor, designed for direct testing from a minimal volume of whole blood, holds significant potential for improving CKD management, offering a portable, reliable alternative for preoperative diagnostics and home-based chronic disease monitoring.
研究领域:
医学工程
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生物医学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Xin Wen,Xin Zhang,Wanting Wang,Fuqiang Zhao,Mingyong Xie,Guomin Pei,Jun Cao,Hesham El-Seedi,Hui Ye,Jun Yang,Yuanping Zheng,Chuan Li
Diabetic kidney disease (DKD) is a severe metabolic disorder that typically results from diabetes mellitus and culminates in chronic kidney disease and renal failure. It has been reported that Holothuria leucospilota polysaccharide (HLP) has an improvement effect on type 2 diabetes mellitus (T2DM) rats. This study aimed to explore the impact of HLP on DKD further and reveal its mechanism. The spontaneous Goto-Kakizaki (GK) rats were used as a model of the DKD group, and Wistar rats were used as a normal control group, treated with intragastric administration for 4 weeks. The results showed that after HLP intervention, the renal index was reduced. Scr, BUN, and UA levels increased in the DKD group, and the HLP-H group was significantly decreased by 15.44 μmol/L, 1.11 mmol/L, and 0.08 mmol/L ( p < 0.05). HLP also alleviated renal pathological damage and kidney fibrosis, decreased MIF, CD74, and IL-6 mRNA expression levels, enhanced PI3K, AKT, and PCX levels. These results indicated that HLP effectively relieved DKD by regulating inflammation and metabolism.
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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PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Lei Du,Sijie Liu,Yinfei Lu,Dongxue Ren,Xiujuan Yu,Yue Hu,Tingting Yang,Qun Yang,Jingxian Ming,Jiawei Zhang,Xiaoxing Yin,Qian Lu
Abnormal proliferation of mesangial cells is a hallmark of diabetic nephropathy (DN). However, the cellular signaling mechanisms that regulate this proliferation remain poorly understood. In this study, it is demonstrated that GA-binding protein (GABP), a member of the ETS family of transcription factors composed of GABPα and GABPβ, plays a significant role in the development of renal fibrosis by modulating mesangial cell proliferation. Notably, the deficiency of GABP in mesangial cells inhibits hyperglycemia-induced proliferation and mitigates renal fibrosis in a murine model of type 2 diabetes mellitus (T2DM). RNA sequencing analysis identifies GLI Family Zinc Finger 1 (GLI1) as the principal downstream effector of GABP in diabetic mice, serving as a crucial regulator of the G1/S transition within the cell cycle. Subsequent investigations have demonstrated that GABP interacts with the GLI1 promoter, facilitating mesangial cell proliferation via GLI1-dependent pathways. This is evidenced by the fact that GLI1 knockdown abrogates the proliferation of mesangial cells with GABP overexpression. Consequently, GABP emerges as a pivotal regulator of renal fibrosis and represents a promising therapeutic target for the treatment of diabetic nephropathy.
研究领域:
分子生物学
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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
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