Hirudin in the Treatment of Chronic Kidney Disease.

Chronic kidney disease (CKD) is a common public health concern. The global burden of CKD is increasing due to the high morbidity and mortality associated with it, indicating the shortcomings of therapeutic drugs at present. Renal fibrosis is the common pathology of CKD, which is characterized by glomerulosclerosis, renal tubular atrophy, and renal interstitial fibrosis. Natural hirudin is an active ingredient extracted from Hirudo medicinalis, which has been found to be the strongest natural specific inhibitor of thrombin. Evidence based on pharmacological data has shown that hirudin has important protective effects in CKD against diabetic nephrology, nephrotic syndrome, and renal interstitial fibrosis. The mechanisms of hirudin in treating CKD are mainly related to inhibiting the inflammatory response, preventing apoptosis of intrinsic renal cells, and inhibiting the interactions between thrombin and protease-activated receptors. In this review, we summarize the function and beneficial properties of hirudin for the treatment of CKD, and its underlying mechanisms.

CPT1A Protects Podocytes From Lipotoxicity and Apoptosis In Vitro and Alleviates Diabetic Nephropathy In Vivo.

Defective fatty acid oxidation (FAO) has been implicated in diabetic kidney disease (DKD), yet little is known about the role of carnitine palmitoyltransferase-1A (CPT1A), a pivotal rate-limiting enzyme of FAO, in the progression of DKD. Here, we investigate whether CPT1A is a reliable therapeutic target for DKD. We first confirmed the downregulation expression of CPT1A in glomeruli from patients with diabetes. We further evaluated the function of CPT1A in diabetic models. Overexpression of CPT1A exhibited protective effects in diabetic conditions, improving albuminuria and glomerular sclerosis as well as mitigating glomerular lipid deposits and podocyte injury in streptozotocin-induced diabetic mice. Mechanistically, CPT1A not only fostered lipid consumption via fatty acid metabolism pathways, thereby reducing lipotoxicity, but also anchored Bcl2 to the mitochondrial membrane, thence preventing cytochrome C release and inhibiting the mitochondrial apoptotic process. Furthermore, a novel transcription factor of CPT1A, FOXA1, was identified. We elucidate the crucial role of CPT1A in mitigating podocyte injury and the progression of DKD, indicating that targeting CPT1A may be a promising avenue for DKD treatment.

Deficiency of Nuclear Receptor Coactivator 3 Aggravates Diabetic Kidney Disease by Impairing Podocyte Autophagy.

Nuclear receptors (NRs) are important transcriptional factors that mediate autophagy, preventing podocyte injury and the progression of diabetic kidney disease (DKD). However, the role of nuclear receptor coactivators that are powerful enhancers for the transcriptional activity of NRs in DKD remains unclear. In this study, a significant decrease in Nuclear Receptor Coactivator 3 (NCOA3) is observed in injured podocytes caused by high glucose treatment. Additionally, NCOA3 overexpression counteracts podocyte damage by improving autophagy. Further, Src family member, Fyn is identified to be the target of NCOA3 that mediates the podocyte autophagy process. Mechanistically, NCOA3 regulates the transcription of Fyn in a nuclear receptor, PPAR-γ dependent way. Podocyte-specific NCOA3 knockout aggravates albuminuria, glomerular sclerosis, podocyte injury, and autophagy in DKD mice. However, the Fyn inhibitor, AZD0530, rescues podocyte injury of NCOA3 knockout DKD mice. Renal NCOA3 overexpression with lentivirus can ameliorate podocyte damage and improve podocyte autophagy in DKD mice. Taken together, the findings highlight a novel target, NCOA3, that protects podocytes from high glucose injury by maintaining autophagy.

Distribution spectrum and clinical significance of glomerular exostosin (EXT1) deposits in PLA2R-positive membranous nephropathy.

BACKGROUND: The discovery of antigen phospholipase A2 receptor (PLA2R) in 2009 ushered in the antigen-based study of membranous nephropathy. The further putative antigen exostosin 1/2 (EXT1/2) was described in 2019. However, the distribution spectrum of glomerular EXT1 deposits in membranous nephropathy has not been fully elucidated. METHODS: We conducted a retrospective cohort study of biopsy-proven membranous nephropathy patients. Patients with complete baseline data and adequate tissue specimens were included in this study. Tests for glomerular expression of PLA2R and EXT1 and circulating anti-PLA2R antibodies were performed. Clinicopathological and outcome data were reviewed. RESULTS: We included 626 patients, namely, 487 (77.8%) PLA2R-positive patients and 54 (8.6%) EXT1-positive patients; 32 (5.1%) patients were dual-positive for PLA2R and EXT1 (PLA2R + /EXT1 +). A higher percentage of dual-positive patients had low C3 levels (P < 0.001) and were more likely to have autoimmune diseases (P = 0.013) than PLA2R-positive and EXT1-negative (PLA2R + /EXT1-) patients. Kidney biopsy findings revealed that there was a higher percentage of glomerular IgG1, IgG2, IgA, C4, and C1q deposits (P < 0.05), "full-house" staining (P < 0.001), and stronger intensity of C1q staining (P = 0.002) in PLA2R + /EXT1 + patients. Based on Kaplan-Meier analysis, a higher percentage of PLA2R + /EXT1 + patients exhibited partial or complete remission of proteinuria. Furthermore, EXT1-positive expression was a favourable predictor for proteinuria remission, whereas interstitial fibrosis/tubular atrophy was an unfavourable predictor. A complement C3 level < 0.79 g/L was independently associated with EXT1 positivity in PLA2R-positive membranous nephropathy. CONCLUSIONS: We describe a subgroup of PLA2R and EXT1 dual-positive patients. Patients in this subset exhibited more signs of autoimmunity and more frequent clinical remission. In PLA2R-positive membranous nephropathy, a complement C3 level < 0.79 g/L was independently associated with EXT1 positivity, which was a favourable predictor for proteinuria remission.

Integrin ß8 prevents pericyte-myofibroblast transition and renal fibrosis through inhibiting the TGF-ß1/TGFBR1/Smad3 pathway in diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the leading causes to develop end-stage kidney disease worldwide. Pericytes are implicated in the development of tissue fibrosis. However, the underlying mechanisms of pericytes in DKD remain largely unknown. We isolated and cultured primary pericytes and rat mesangial cells (HBZY-1). Western blot and qRT-PCR analysis were used to explore the role and regulatory mechanism of Integrin ß8/transforming growth factor beta 1 (TGF-ß1) pathway. We also constructed pericyte-specific Integrin ß8 knock-in mice as the research objects to determine the role of Integrin ß8 in vivo. We discovered that reduced Integrin ß8 expression was closely associated with pericyte transition in DKD. Overexpressed Integrin ß8 in pericytes dramatically suppressed TGF-ß1/TGF beta receptor 1 (TGFBR1)/Smad3 signaling pathway and protected glomerular endothelial cells (GECs) in vitro. In vivo, pericyte-specific Integrin ß8 knock-in ameliorated pericyte transition, endothelium injury and renal fibrosis in STZ-induced diabetic mice. Mechanistically, Murine double minute 2 (MDM2) was found to increase the degradation of Integrin ß8 and caused TGF-ß1 release and activation. Knockdown MDM2 could partly reverse the decline of Integrin ß8 and suppress pericytes transition. In conclusion, the present findings suggested that upregulated MDM2 expression contributes to the degradation of Integrin ß8 and activation of TGF-ß1/TGFBR1/Smad3 signaling pathway, which ultimately leads to pericyte transition during DKD progression. These results indicate MDM2/Integrin ß8 might be considered as therapeutic targets for DKD.

Asparagine endopeptidase protects podocytes in adriamycin-induced nephropathy by regulating actin dynamics through cleaving transgelin.

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.

Decreased DANCR contributes to high glucose-induced extracellular matrix accumulation in human renal mesangial cell via regulating the TGF-ß/Smad signaling.

Glomerulosclerosis is one of the major histopathologic changes in diabetic kidney diseases (DKD), which is characterized by excessive deposition of extracellular matrix (ECM) in the glomerulus mainly produced by mesangial cells in response to transforming growth factor-ß (TGF-ß) stimuli under diabetic conditions. Despite TGF-ß has been implicated as a major pathogenic factor in the development of diabetic glomerulosclerosis, clinical trials of monoclonal antibodies against TGF-ß failed to demonstrate therapeutic benefits. Thus, developing alternative therapeutic strategies to effectively block the TGF-ß/Smad signaling could be of paramount importance for DKD treatment. Emerging evidence indicates that dysregulation of certain lncRNAs can lead to aberrant activation of TGF-ß/Smad signaling. Herein, we identified a novel lncRNA, named DANCR, which could efficiently function as a negative regulator of TGF-ß/Smad signaling in mesangial cells. Ectopic expression of DANCR could specifically block the activation of TGF-ß/Smad signaling induced by high-glucose or TGF-ß in human renal mesangial cells (HRMCs). Mechanistically, DANCR functions to stabilize nemo-like kinase (NLK) mRNA through interaction with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), resulting in enhanced phosphorylating on the linker region of activated Smad2/3 in the nucleus. Taken together, our data have uncovered an lncRNA-based regulatory modality of the TGF-ß/Smad signaling and identified DANCR as an endogenous blocker of TGF-ß/Smad signaling in HRMCs, which may represent a potential therapeutic target against the diabetic glomerulosclerosis.

Cellular phenotypic transitions in diabetic nephropathy: An update.

Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetes and is the most common cause of end stage renal disease (ESRD). Renal fibrosis is the final pathological change in DN. It is widely believed that cellular phenotypic switching is the cause of renal fibrosis in diabetic nephropathy. Several types of kidney cells undergo activation and differentiation and become reprogrammed to express markers of mesenchymal cells or podocyte-like cells. However, the development of targeted therapy for DN has not yet been identified. Here, we discussed the pathophysiologic changes of DN and delineated the possible origins that contribute to myofibroblasts and podocytes through phenotypic transitions. We also highlight the molecular signaling pathways involved in the phenotypic transition, which would provide valuable information for the activation of phenotypic switching and designing effective therapies for DN.

Regulation of Podocyte Injury by CircHIPK3/FUS Complex in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus and is one of the leading causes of end-stage kidney disease. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that play important roles in various diseases, yet their roles in DKD are poorly understood. CircRNA HIPK3 (circHIPK3), a highly conserved circRNA, is closely related to various cellular functions, including cell proliferation and apoptosis. The association between circHIPK3 and diabetic complications has been well demonstrated in multiple previous studies. However, the role of circHIPK3 in podocyte injury in DKD remains unclear. Herein, we discovered that circHIPK3 expression is markedly elevated in cultured podocytes under high-glucose (HG) conditions and glomeruli of diabetic mice, which is closely associated with podocyte injury in DKD. Functionally, lentivirus-mediated knockdown of circHIPK3 dramatically suppresses HG-induced podocyte apoptosis in vitro. Therapeutically, silencing circHIPK3 by adeno-associated virus-mediated RNA interference ameliorates podocyte injury and albuminuria in STZ-induced diabetic mice. Mechanistically, circHIPK3 facilitates the enrichment of fused in sarcoma (FUS) on the ectodysplasin A2 receptor (EDA2R) promoter, resulting in the upregulation of EDA2R expression and activation of apoptotic signaling. Taken together, these results indicate circHIPK3/FUS/EDA2R axis as a therapeutic target for podocyte injury and DKD progression.

Flavonoids in Treatment of Chronic Kidney Disease.

Chronic kidney disease (CKD) is a progressive systemic disease, which changes the function and structure of the kidneys irreversibly over months or years. The final common pathological manifestation of chronic kidney disease is renal fibrosis and is characterized by glomerulosclerosis, tubular atrophy, and interstitial fibrosis. In recent years, numerous studies have reported the therapeutic benefits of natural products against modern diseases. Substantial attention has been focused on the biological role of polyphenols, in particular flavonoids, presenting broadly in plants and diets, referring to thousands of plant compounds with a common basic structure. Evidence-based pharmacological data have shown that flavonoids play an important role in preventing and managing CKD and renal fibrosis. These compounds can prevent renal dysfunction and improve renal function by blocking or suppressing deleterious pathways such as oxidative stress and inflammation. In this review, we summarize the function and beneficial properties of common flavonoids for the treatment of CKD and the relative risk factors of CKD.

IL (Interleukin)-17A Acts in the Brain to Drive Neuroinflammation, Sympathetic Activation, and Hypertension.

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Novel prognostic prediction model constructed through machine learning on the basis of methylation-driven genes in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is a common tumor with poor prognosis and is closely related to many aberrant gene expressions. DNA methylation is an important epigenetic modification mechanism and a novel research target. Thus, exploring the relationship between methylation-driven genes and KIRC prognosis is important. The methylation profile, methylation-driven genes, and methylation characteristics in KIRC was revealed through the integration of KIRC methylation, RNA-seq, and clinical information data from The Cancer Genome Atlas. The Lasso regression was used to establish a prognosis model on the basis of methylation-driven genes. Then, a trans-omics prognostic nomogram was constructed and evaluated by combining clinical information and methylated prognosis model. A total of 242 methylation-driven genes were identified. The Gene Ontology terms of these methylation-driven genes mainly clustered in the activation, adhesion, and proliferation of immune cells. The methylation prognosis prediction model that was established using the Lasso regression included four genes in the methylation data, namely, FOXI2, USP44, EVI2A, and TRIP13. The areas under the receiver operating characteristic curve of 1-, 3-, and 5-year survival rates were 0.810, 0.824, and 0.799, respectively, in the training group and 0.794, 0.752, and 0.731, respectively, in the testing group. An easy trans-omics nomogram was successfully established. The C-indices of the nomogram in the training and the testing groups were 0.8015 and 0.8389, respectively. The present study revealed the overall perspective of methylation-driven genes in KIRC and can help in the evaluation of the prognosis of KIRC patients and provide new clues for further study.

Bioinformatic analysis reveals that the OAS family may play an important role in lupus nephritis.

BACKGROUND: Lupus nephritis (LN) is a common complication of systemic lupus erythematosus that presents a high risk of end-stage renal disease. However, the molecular mechanisms of LN remain unclear. The lack of understanding hinders the development of specific targeted therapy for this progressive disease. OBJECTIVES: In the present study, we used bioinformatics analysis of gene expression profiles from the Gene Expression Omnibus to identify novel targets and potential biomarkers for LN. MATERIAL AND METHODS: A GSE32591 dataset, which included 31 LN glomerular biopsy tissues and 14 living donors' glomerular tissues, was downloaded for further analysis. Differentially expressed genes in LN were analyzed by the limma package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for the differentially expressed genes by using the Disease Ontology Semantic and Enrichment and the clusterProfiler software. The protein-protein interaction (PPI) network was then formed using STRING online tool. RESULTS: 440 genes, including 310 upregulated genes and 130 downregulated genes, were found as differentially expressed genes. GO and KEGG analyses revealed that immune response is significantly enriched in such genes. The PPI network showed that ISG15, MX1, OAS1, OAS2, and OAS3 were the hub genes enriched in LN. Along with literature review, the OAS family genes were revealed to be closely associated with LN progression. CONCLUSIONS: our studies provided new insight into the molecular pathogenesis of LN. The OAS family may play an important role in LN and act as a novel molecular candidate for the further study of LN.

Transcriptome sequencing of circular RNA reveals a novel circular RNA-has_circ_0114427 in the regulation of inflammation in acute kidney injury.

Acute kidney injury (AKI) is a common serious syndrome characterized by rapid decrease of glomerular filtration rate and the progressive increase of serum creatinine. Circular RNAs (circRNAs) are regulatory RNAs that recently became popular among various diseases. However, the expression profile and function of circRNAs in AKI remain largely unknown. The main function of circRNAs is acting as competing endogenous RNAs (ceRNAs) by binding with microRNAs (miRNAs), as indicated by recent research. In the present study, we established cisplatin-induced AKI model in mice and isolated renal tubular tissues to extract circRNAs for next-generation sequencing (NGS) and bioinformatics analysis. We analyzed the composition, distribution and Gene Ontology terms of circRNAs in cisplatin-induced AKI and revealed differentially expressed circRNAs related to AKI. By finding homologous genes between mouse and human, we identified circRNA- circ-0114427 in humans. We further investigated its function in AKI cell model. Circ-0114427 expression was significantly up-regulated in different AKI cell models. Knockdown of circ-0114427 indicated that circ-0114427 bound to miR-494 as a miRNA sponge to regulate ATF3 expression and further affected the expression of downstream cytokine IL-6. Circ-0114427 regulates inflammatory progression in AKI's early stage via circ-0114427/miR-494/ATF3 pathway. Our findings reveal the expression profile of circRNAs in cisplatin-induced AKI and provide a novel insight into the regulatory mechanism of circRNAs, which may become a new molecular target resource for early diagnosis and treatment strategies.

Immune cell infiltration characteristics and related core genes in lupus nephritis: results from bioinformatic analysis.

BACKGROUND: Lupus nephritis (LN) is a common complication of systemic lupus erythematosus that presents a high risk of end-stage renal disease. In the present study, we used CIBERSORT and gene set enrichment analysis (GSEA) of gene expression profiles to identify immune cell infiltration characteristics and related core genes in LN. RESULTS: Datasets from the Gene Expression Omnibus, GSE32591 and GSE113342, were downloaded for further analysis. The GSE32591 dataset, which included 32 LN glomerular biopsy tissues and 14 glomerular tissues from living donors, was analyzed by CIBERSORT. Different immune cell types in LN were analyzed by the Limma software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis based on GSEA were performed by clusterProfiler software. Lists of core genes were derived from Spearman correlation between the most significant GO term and differentially expressed immune cell gene from CIBERSORT. GSE113342 was employed to validate the association between selected core genes and clinical manifestation. Five types of immune cells revealed important associations with LN, and monocytes emerged as having the most prominent differences. GO and KEGG analyses indicated that immune response pathways are significantly enriched in LN. The Spearman correlation indicated that 15 genes, including FCER1G, CLEC7A, MARCO, CLEC7A, PSMB9, and PSMB8, were closely related to clinical features. CONCLUSIONS: This study is the first to identify immune cell infiltration with microarray data of glomeruli in LN by using CIBERSORT analysis and provides novel evidence and clues for further research of the molecular mechanisms of LN.

Integrated bioinformatics analysis reveals novel hub genes closely associated with pathological mechanisms of immunoglobulin A nephropathy.

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common glomerular disease. The major pathological changes associated with it affect cell proliferation, fibrosis, apoptosis, inflammation and extracellular matrix (ECM) organization. However, the molecular events underlying IgAN remain to be fully elucidated. In the present study, an integrated bioinformatics analysis was applied to further explore novel potential gene targets for IgAN. The mRNA expression profile datasets GSE93798 and GSE37460 were downloaded from the Gene Expression Omnibus database. After data preprocessing, differentially expressed genes (DEGs) were identified. Gene Ontology (GO) enrichment analysis of DEGs was performed. Protein-protein interaction (PPI) networks of the DEGs were built with the STRING online search tool and visualized by using Cytoscape, and hub genes were identified through the degree of connectivity in the PPI. The hub genes were subjected to Kyoto Encyclopedia of Genes and Genomes pathway analysis, and co-expression analysis was performed. A total of 298 DEGs between IgAN and control groups were identified, and 148 and 150 of these DEGs were upregulated and downregulated, respectively. The DEGs were enriched in distinct GO terms for Biological Process, including cell growth, epithelial cell proliferation, ERK1 and ERK2 cascades, regulation of apoptotic signaling pathway and ECM organization. The top 10 hub genes were then screened from the PPI network by Cytoscape. As novel hub genes, Fos proto-oncogene, AP-1 transcription factor subunit and early growth response 1 were determined to be closely associated with apoptosis and cell proliferation in IgAN. Tumor protein 53, integrin subunit ß2 and fibronectin 1 may also be involved in the occurrence and development of IgAN. Co-expression analysis suggested that these hub genes were closely linked with each other. In conclusion, the present integrated bioinformatics analysis provided novel insight into the molecular events and novel candidate gene targets of IgAN.

Brain TACE (Tumor Necrosis Factor-α-Converting Enzyme) Contributes to Sympathetic Excitation in Heart Failure Rats.

TNF-α (tumor necrosis factor-α) is initially synthesized as a transmembrane protein that is cleaved by TACE (TNF-α-converting enzyme) to release soluble TNF-α. The elevated level of TNF-α in the brain and circulation in heart failure (HF) suggests an increase in the TACE-mediated ectodomain shedding process. The present study sought to determine whether TACE is upregulated in cardiovascular/autonomic brain regions like subfornical organ and hypothalamic paraventricular nucleus in rats with ischemia-induced HF and whether TACE plays a role in TNF-α-driven sympathetic excitation. We found that TACE was expressed throughout the subfornical organ and paraventricular nucleus, with significantly higher levels in HF than in sham-operated (Sham) rats. Intracerebroventricular injection of recombinant TACE induced a mild increase in blood pressure, heart rate, and renal sympathetic nerve activity that peaked at 15 to 20 minutes in both Sham and HF rats. HF rats had a secondary prolonged increase in these variables that was prevented by the TNF-α inhibitor SPD304. Intracerebroventricular administration of the TACE inhibitor TNF-alpha protease inhibitor 1 decreased blood pressure, heart rate, and renal sympathetic nerve activity in Sham and HF rats, with an exaggerated reduction in heart rate and renal sympathetic nerve activity in the HF rats. Direct microinjection of TACE or TNF-alpha protease inhibitor 1 into paraventricular nucleus or subfornical organ of Sham and HF rats elicited blood pressure, heart rate, and renal sympathetic nerve activity responses similar to intracerebroventricular TACE or TNF-alpha protease inhibitor 1. Intracerebroventricular infusion of Ang II (angiotensin II) and IL (interleukin)-1ß increased TACE expression in subfornical organ and paraventricular nucleus of normal rats. These data suggest that a TACE-mediated increase in soluble TNF-α in the brain contributes to sympathetic excitation in HF.

Bioinformatic analysis reveals novel hub genes and pathways associated with hypertensive nephropathy.

AIM: Hypertensive nephropathy (HTN) is one of the leading causes of end-stage renal disease and is closely associated with inflammation and tubule-interstitial fibrosis. The molecular mechanism underlying HTN remains unclear. This study used bioinformatic analysis to identify the novel gene targets for HTN. METHODS: We downloaded the microarray data of GSE99325 and GSE32591 from Gene Expression Omnibus. The dataset comprised 20 HTN and 15 normal samples. The differentially expressed genes (DEG) were identified, and then gene ontology (GO) enrichment was performed, and a GO tree was constructed by using clusterProfiler and ClueGO. In addition, a protein-protein interaction network was established using the Search Tool for the Retrieval of Interacting Genes database and visualized by Cytoscape. The novel hub genes were validated in in vitro experiments. RESULTS: A total of 267 genes (117 up-regulated and 150 down-regulated genes) were identified as DEG. GO analysis and the GO tree indicated that the DEG were mainly associated with steroid hormone response and the extracellular matrix. Based on the protein-protein interaction network, we screened out several novel hub genes. Considering the findings and the literature review, we focused on and validated the dual specificity phosphatase 1, tissue inhibitor of matrix metalloproteinases 1, fos proto-oncogene and jun proto-oncogenes, which may play significant roles in the pathogenesis of HTN. These findings were consistent with the bioinformatic results for the in vitro validation. CONCLUSION: This study identified for the first time novel hub genes with microarray data in HTN by using bioinformatic analysis and provided novel evidence and clues for future works.

Bioinformatic Analysis Reveals Novel Immune-Associated Hub Genes in Human Membranous Nephropathy.

BACKGROUND: Membranous nephropathy (MN) is one of the most common pathologies of the nephrotic syndrome. MN is closely associated with the autoimmune response but its molecular mechanism remains unclear. Bioinformatic network analysis can be used to identify disease-related hub genes. METHODS: The microarray data set GSE47183 of patients with MN containing 21 MN samples and 13 control samples that were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using the limma package. Thereafter, gene ontology (GO) enrichment was performed for DEGs using the clusterProfiler package. The protein-protein interaction (PPI) network was established through the Search Tool for the Retrieval of Interacting Genes database and visualized using Cytoscape. Finally, the hub genes were identified through the maximal clique centrality method. RESULT: A total of 642 DEGs were recognized, consisting of 458 upregulated genes and 184 downregulated genes. GO enrichment analysis indicates that DEGs for MN are mainly related to antigen processing and presentation. For the PPI network, we identified approximately nine hub genes. Considering data from the literature, we ultimately identified PSMB8 as a novel hub gene, which could play a significant role in the occurrence and development of MN. CONCLUSION: This study is the first to identify novel hub genes with transcriptome microarray data in MN using bioinformatics. The newly discovered hypothetical hub genes should be functionally tested to determine if they truly play an etiologic role in MN.

PYCARD Gene Plays a Key Role in Rapidly Progressive Glomerulonephritis: Results of a Weighted Gene Co-Expression Network Analysis.

BACKGROUND: Rapidly progressive glomerulonephritis (RPGN) is caused by various diseases process, thereby resulting in extensive crescent formation, which could lead to a rapid loss of kidney function. The molecular pathogenesis of RPGN remains largely unknown and requires clarification. The weighted gene co-expression network analysis (WGCNA) is a powerful bioinformatics tool to identify meaningful molecules in diseases. METHODS: The dataset of GSE104948, which contains 22 RPGN and 18 normal samples, was obtained from Gene Expression Omnibus database. After data pre-processing, the WGCNA was performed to successfully cluster several significant modules. The most significant module was selected for further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Visualization of network and screening of hub genes were performed by using Cytoscape software. RESULTS: A total of 11 modules were clustered by WGCNA, and the most significant module-turquoise module was selected. As discovered via GO enrichment and KEGG pathway analysis, the turquoise module was mainly associated with neutrophil activation and degranulation. After visualization and calculation for the network, the PYCARD gene has higher relationship score in 2 clusters, namely, neutrophil activation and degranulation. In accordance with the literature review, the hub gene could be closely related to the inflammation response and could act as the potential therapeutic targets in RPGN. CONCLUSIONS: WGCNA in RPGN expression profiling was used for the first time in this paper. A novel hub gene closely associated with RPGN was screened out, thereby providing the brand-new molecular candidate for RPGN.