Partial epithelial-to-mesenchymal transition (EMT) and T cell-mediated inflammation in hypertensive and diabetic nephropathy
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE166239 | GEO | 2023/12/01
REPOSITORIES: GEO
Similar Datasets
Project description:Background and Objective: Hypertensive nephropathy (HN) requires a kidney biopsy as gold-standard for its diagnosis but histological findings are not entirely specific and lack specific prognostic markers. We aimed at defining prognostic candidate markers based on glomerular protein signatures. Method: We included adult patients (n=17) with an eGFR >30 ml/min/1.73m2 and proteinuria <3g/d from the Norwegian Kidney Biopsy Registry: stable patients (n=9) and subjects with HN progression (n=8) leading to end-stage renal disease (ESRD) within 20 years of follow-up. Glomerular cross-sections were microdissected from archival kidney biopsy sections and processed for protein extraction. Proteomic analyses were performed using Q-exactive HF mass spectrometer and relative glomerular protein abundance were compared between progressive vs non-progressive patients. Results: Amongst 1870 quality filtered proteins, we identified 58 proteins with an absolute fold change (FC)>1.5, p<0.05, including 17 proteins with absolute FC >2, indicative of HN progression (highest FC: Cadherin 16 and UDP-glucuronosyl-transferase 2B7). Hierarchical cluster and principal component analysis (PCA) with the 17 proteins showed clear separation of samples into HN progressors and non-progressors. Supervised classifier analysis (K nearest neighbour) identified a set of five proteins which classified 16/17 samples correctly. Applying Geneset Enrichment Analysis (GSEA), in general metabolic pathways were enriched in progressors, and structural cell pathways enriched in non-progressors. Pathway analysis identified Epithelial Adherens Junction Signaling as the most affected canonical pathway. The signature of HN progression is different from the respective signature of IgA progression. Conclusion: Glomerular proteomic profiling can be used to discriminate progressors from non-progressors in HN.
2023-05-23 | PXD026709 | Pride
Project description:Studies of diabetic glomerular injury raise the possibility of developing useful early biomarkers and therapeutic approaches for the treatment of type 2 diabetic nephropathy (T2DN). In this study, it is found that FGF13 expression is induced in glomerular endothelial cells (GECs) during T2DN progression, and endothelial-specific deletion of Fgf13 potentially alleviates T2DN damage. Fgf13 deficiency restores the expression of Parkin both in the cytosolic, mitochondrial, and nuclear fractions under diabetic conditions, resulting in improved mitochondrial homeostasis and endothelial barrier integrity due to promotion of mitophagy and inhibition of apoptosis. Additionally, it is confirmed that the beneficial effects of Fgf13 deficiency on T2DN are abolished by endothelial-specific double deletion of Fgf13 and Prkn. The effects of Fgf13 deficiency on mitophagy and apoptosis via Parkin-dependent regulation may be distinct and separable events under diabetic conditions. These data show that the bifunctional role of Fgf13 deficiency in promoting mitophagy and inhibiting apoptosis through Parkin can shape mitochondrial homeostasis regulation in GECs and T2DN progression. Acting as a potential biomarker and therapeutic target for prevention and control of T2DN, mechanistically understanding of the biofunction of FGF13 may also be of relevance to the pathogenesis of other FGF13- and Parkin-associated diseases.
2024-12-11 | GSE192889 | GEO
Project description:Hypertensive nephropathy (HTN) emerges as one of the leading causes of end-stage renal disease, yet the precise mechanisms and cell-specific gene expression changes are still unknown. This study used single-cell RNA sequencing (scRNA-seq) to explore novel molecular mechanisms and hub gene targets for HTN.Our data identifies a distinct cell-specific gene expression profile, pathogenic signaling pathways and potential cell-cell crosstalks in the progression of HTN. These findings will provide a promising novel landscape for mechanisms and treatment of HTN.
2023-08-31 | GSE210898 | GEO
Project description:The histologic diagnosis of idiopathic IgA Nephopathy (IgAN) is based o renal lesions scores. Aim of our study was to identify specific gene expression changes that characterize active renal lesions that may be more responsive to immunosuppressive therapy than chronic lesions. Total RNA was extracted from archival FFPE renal tissue samples of 55 IgAN patients, 31 non-IgAN patients. IgAN patients were accurately stratified based on the LUMPED classifications. Genome-wide gene expression profiles were generated and Oneway ANOVA with tukeyHSD post hoc testing was used to identify specific transcripts associated with active and chronic renal lesions in IgAN. RT-PCR was used to validate selected transcripts. Immunohistochemistry (IHC) was used to evaluate specific protein expression in biopsy specimens. Bioinfomatic analysis identified 183 genes with a Fold Change > 1.5 exclusively modulated in IgAN biopsies with active lesions and 162 genes with Fold Change > 1.5 exclusively modulated in IgAN biopsies with chronic lesions. These genes belonged to renal cellular damage and immune system regulatory pathways. To establish the validity of gene expression determined by microarray analysis, we performed RT-PCR on genes that were putatively involved in generating active and chronic lesions that may be involved in activating local inflammatory response and contributing to renal damage. Validated transcripts were also confirmed at protein level with IHC on kidney biopsy specimens. Transcriptomics on FFPE renal biopsies integrates histomorphologic renal lesions. Our study identifies specific gene expression changes involved in active and chronic lesions at the time of renal biopsy. This novel information may be used for personalized therapy through a system pharmacology approach to identify targeted molecules able to revert aberrant expression networks characterizing active and chronic lesions.
2020-06-02 | GSE115857 | GEO
Project description:Natural flavonoid pectolinarigenin (PEC) was reported to alleviate tubulointerstitial fibrosis of unilateral ureteral obstruction (UUO) mice in our previous study. To further investigate nephroprotective effects of PEC in hyperuricemic nephropathy (HN), adenine and potassium oxonate induced HN mice and uric acid-treated mouse kidney epithelial (TCMK-1) cells were employed in the study. As a result, PEC significantly lowered serum uric acid level and restored hyperuricemia-related kidney injury in HN mice. Meanwhile, PEC alleviated inflammation, fibrosis and reduced adipokine FABP4 content in the kidneys of HN mice and uric acid-treated TCMK-1 cells. Mechanistically, PEC inhibited the TGF-β1 expression as well as the phosphorylation of transcription factor SMAD3 and STAT3 to regulate the corresponding inflammatory and fibrotic gene expression in kidney tissues. In conclusion, our results suggested that PEC could inhibit the activation of SMAD3 and STAT3 signaling to suppress inflammation and fibrosis, thereby alleviate HN in mice.
2022-02-18 | GSE190205 | GEO
Project description:MicroRNAs (miRNAs) are small regulatory RNA molecules that modulate the activity of specific mRNA targets and play important roles in a wide range of physiologic and pathologic processes. We hypothesized that miRNAs might be involved in the progression of CKD. In our previous studies we found chronic renal damages developed progressively in rats with 5/6 nephrectomy. L-mimosine(L-Mim) intervention from wk 5 to wk 12 improved renal function and resulted in additional accumulation of HIF-1 M-NM-1 and -2 M-NM-1 at wk 12. In the current study we found miR-29c was up-regulated in the L-Mim treated group compared with the control using Agilent miRNA microarrays. Of the microRNAs and proteins that exhibited reciprocal changes in expression following the L-Mim treatment, miR-29c and tropomyosin 1M-NM-1 (TPM1), which is involved in stress fiber function, met the sequence criteria for microRNA-target interaction, were later confirmed by 3'-untranslated region reporter analysis. TGFM-NM-21 treatment (3 ng/ml, 24 hours) decreased miR-29c expression and up-regulated protein expression of TPM1 in human renal epithelial cells. Overexpression of miR-29c significantly attenuated TGF-M-NM-21 induced increase in TPM1 in vitro. Moreover, intrarenal expression of miR-29c was decreased in IgAN patients with moderate to severe tubulointerstital fibrosis (TIF), compared with IgAN patients without TIF, and intrarenal protein expression of TMP1 was significantly increased in IgAN patients with TIF. The results suggest that intrarenal expression of miR-29c was down-regulated while its predicted target, TPM1 was up-regulated in the progression of CKD. Short term stabilizing of HIF up-regulates miR-29c and attenuates CKD in the remnant kidney model. Four weeks after 5/6 nephrectomy, rats were treated with intraperitoneal injections of vehicle or L-mimosine (L-Mim, Calbiochem), a prolyl 4-hydroxylase inhibitor (PHD), at a dosage of 50 mg/kg every other day. At the end of wk 12 after 5/6 nephrectomy, all rats (n=4, for each group) were sacrificed and blood samples were collected via cardiac puncture. Renal tissue were harvested, one piece of which was fixed in neutral formalin and then embedded in paraffin. The remaining kidney tissue was dissected in ice-cold PBS to, remove medulla, and then snap-frozen in liquid nitrogen before transferring to storage at -80M-BM-0C until further analysis.
2013-01-08 | E-GEOD-28471 | biostudies-arrayexpress
Project description:Enrolled 24 participants, including twelve renal biopsy-proven T2DN and twelve T2DM, and isolated uEV s by ultracentrifugation to perform adequate parallel microarrays for mRNAs, lncRNAs and circRNAs and sequencing for miRNAs.One hundred mL of first-morning urine was collected.All urine samples were retained and immediately transferred to the laboratory and centrifuged at 2500 x g at 4°C for 15 min using a horizontal rotor (Dynamica V14R Pro, UK) and at 17,000 x g at 4°C for 40 min using a fixed angle rotor (FA15C rotor, Dynamica, UK). Supernatants were filtered using 0.22µm PES filters (Jet Bio-Filtration, Guangzhou, China) and transferred to new centrifuge tubes and stored at -80 degrees. After overnight melting through a 4 degree, ultracentrifuged at 200,000 xg at 4°C for 2h in a fixed angle P45AT rotor (k factor= 130, CP100NX, Hitachi, Tokyo, Japan) and repeat again after resuspending the pellet in PBS. Supernatants were discarded and the pellets were washed in PBS to obtain the uEVs.
2023-11-27 | GSE218929 | GEO
Project description:Chronic kidney disease (CKD) remains a tremendous and growing burden on the healthcare system and new therapies are needed to prevent or slow disease progression. Metabolic dysregulation and mitochondrial dysfunction are important features of acute and chronic tissue injury across species, and human genetics and preclinical data suggest that the master metabolic regulator 5'-adenosine monophosphate activated protein kinase (AMPK) may be an effective therapeutic target for CKD. Merck has recently disclosed a pan-AMPK activator MK-8722 which was shown to have beneficial effects on metabolic parameters in preclinical models. In this study we investigate the effects of MK-8722 in a progressive model of diabetic nephropathy to determine whether activation of AMPK would be of therapeutic benefit. We find that MK-8722 administration in a therapeutic paradigm is profoundly reno-protective. We provide evidence that the therapeutic effects may be mediated by modulation of renal mitochondrial quality control as well as by attenuating fibrotic and lipotoxic mechanisms in kidney cells. These data further validate the concept that targeting metabolic dysregulation in CKD could be a potential therapeutic approach.
2019-07-25 | GSE134804 | GEO
Project description:Background: Hyperglycemia-induced transcriptional alterations lead to aberrant synthesis of a large number of pathogenetic molecules leading to functional and structural damage to multiple end organs including the kidneys. Diabetic nephropathy (DN) remains a major cause of end stage renal disease. Multiple epigenetic mechanisms, including alteration of long non-coding RNAs (lncRNAs) may play a significant role mediating the cellular transcriptional activities. We have previously shown that lncRNA ANRIL may mediate diabetes associated molecular, functional and structural abnormalities in DN. Here we explored downstream mechanisms of ANRIL alteration in DN. Methods: We used renal cortical tissues from ANRIL knockout (KO) mice and wild type (WT) mice, with or without streptozotocin (STZ) induced diabetes for RNA sequencing. The differentially expressed genes were identified using edgeR and DESeq2 computational methods. KEGG and Reactome pathway analyses and network analyses using STRING and IPA were subsequently performed. Results: Diabetic animals showed hyperglycemia, reduced body weight gain, polyuria and increased urinary albumin. Both albuminuria and polyuria were corrected in the KO diabetic mice. RNA analyses showed Diabetes induced alterations of a large number of transcripts in the wild type (WT) animals. ANRIL knockout (KO) prevented a large number of such alterations. The altered transcripts include metabolic pathways, apoptosis, extracellular matrix protein synthesis and degradation, NFKB related pathways, AGE-RAGE interaction pathways etc. ANRIL KO prevented majority of these pathways. Conclusion: These findings suggest that as ANRIL regulates a large number of molecules of pathogenetic significance, it may potentially be a drug target for DN and other chronic diabetic complications.
2022-03-06 | GSE197699 | GEO
Project description:A microarray analysis with renal biopsy specimens from CKD patients was conducted in order to identify the responsible genes associated with tubulointerstitial fibrosis and tubular cell injury in CKD. This study showed microarray profiles in total 53 biopsy specimens of CKD patients. In the discovery set, 554 down-regulated and 226 up-regulated signatures were identified. Then, the expressional changes of these genes were examined in the validation set. Gene expression profiles in human chronic kidney disease was explored using renal biopsy specimens. Two independent studies: discovery set and validation set were performed. This dataset is part of the TransQST collection.
2015-08-16 | E-GEOD-66494 | biostudies-arrayexpress