Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Krυppel-like factor 15 suppresses renal glomerular mesangial cell proliferation via enhancing P53 SUMO1 conjugation.

ABSTRACT: Mesangial cell (MC) proliferation is a key pathological feature in a number of common human renal diseases, including mesangial proliferative nephritis and diabetic nephropathies. Knowledge of MC responses to pathological stimuli is crucial to the understanding of these disease processes. We previously determined that Krϋppel-like factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, was required for inhibition of MC proliferation. In the present study, we investigated the direct target gene and the underlying mechanism by which KLF15 regulated mesangial proliferation. First, we screened small ubiquitin-related modifier 1 (SUMO1) as the direct transcriptional target of KLF15 and validated this finding with ChIP-PCR and luciferase assays. Furthermore, we demonstrated that overexpressing KLF15 or SUMO1 enhanced the stability of P53, which blocked the cell cycle of human renal MCs (HRMCs) and therefore abolished cell proliferation. Conversely, knockdown of SUMO1 in HRMCs, even those overexpressed with KLF15, could not inhibit HRMC proliferation rates and increase SUMOylation of P53. Finally, the results showed that the levels of SUMOylated P53 in the kidney cortices of anti-Thy 1 model rats were decreased during proliferation periods. These findings reveal the critical mechanism by which KLF15 targets SUMO1 to mediate the proliferation of MCs.

SUBMITTER: Wu L

PROVIDER: S-EPMC8184688 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Corosolic acid inhibits the proliferation of glomerular mesangial cells and protects against diabetic renal damage.

Project description:Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM). This study aimed to explore the effects of corosolic acid (CA) on the renal damage of DM and the mechanisms behind these effects. The renoprotective effect of CA was investigated in type 1 diabetic rats and db/db mice. The kidneys and glomerular mesangial cells (GMCs) were used to study the proliferation of GMCs by immunostaining and MTT assay. Further immunoblotting, siRNA, qPCR analysis, and detecting of NADPH oxidase activity and reactive oxygen species (ROS) generation were performed to explore relevant molecular mechanisms. In CA-treated diabetic animals, diabetes-induced albuminuria, increased serum creatinine and blood urea nitrogen were significantly attenuated, and glomerular hypertrophy, mesangial expansion and fibrosis were ameliorated. Furthermore, CA significantly inhibited proliferation of GMCs and phosphorylation of ERK1/2 and p38 MAPK in both diabetic animals and high glucose (HG)-induced GMCs. CA also normalized ??m and inhibited HG-induced NADPH oxidase activity, ROS generation and NOX4, NOX2, p22(phox) and p47(phox) expression. More importantly, CA inhibited GMC proliferation mediated by NADPH/ERK1/2 and p38 MAPK signaling pathways. These findings suggest that CA exert the protective effect on DN by anti-proliferation resulted from inhibition of p38 MAPK- and NADPH-mediated inactivation of ERK1/2.

| S-EPMC4882506 | biostudies-literature

Analysis of SUMO1-conjugation at synapses.

Project description:SUMO1-conjugation of proteins at neuronal synapses is considered to be a major post-translational regulatory process in nerve cell and synapse function, but the published evidence for SUMO1-conjugation at synapses is contradictory. We employed multiple genetic mouse models for stringently controlled biochemical and immunostaining analyses of synaptic SUMO1-conjugation. By using a knock-in reporter mouse line expressing tagged SUMO1, we could not detect SUMO1-conjugation of seven previously proposed synaptic SUMO1-targets in the brain. Further, immunostaining of cultured neurons from wild-type and SUMO1 knock-out mice showed that anti-SUMO1 immunolabelling at synapses is non-specific. Our findings indicate that SUMO1-conjugation of synaptic proteins does not occur or is extremely rare and hence not detectable using current methodology. Based on our data, we discuss a set of experimental strategies and minimal consensus criteria for the validation of SUMOylation that can be applied to any SUMOylation substrate and SUMO isoform.

| S-EPMC5493437 | biostudies-literature

Renal stromal miRNAs are required for normal nephrogenesis and glomerular mesangial survival.

Project description:MicroRNAs are small noncoding RNAs that post-transcriptionally regulate mRNA levels. While previous studies have demonstrated that miRNAs are indispensable in the nephron progenitor and ureteric bud lineage, little is understood about stromal miRNAs during kidney development. The renal stroma (marked by expression of FoxD1) gives rise to the renal interstitium, a subset of peritubular capillaries, and multiple supportive vascular cell types including pericytes and the glomerular mesangium. In this study, we generated FoxD1(GC);Dicer(fl/fl) transgenic mice that lack miRNA biogenesis in the FoxD1 lineage. Loss of Dicer activity resulted in multifaceted renal anomalies including perturbed nephrogenesis, expansion of nephron progenitors, decreased renin-expressing cells, fewer smooth muscle afferent arterioles, and progressive mesangial cell loss in mature glomeruli. Although the initial lineage specification of FoxD1(+) stroma was not perturbed, both the glomerular mesangium and renal interstitium exhibited ectopic apoptosis, which was associated with increased expression of Bcl2l11 (Bim) and p53 effector genes (Bax, Trp53inp1, Jun, Cdkn1a, Mmp2, and Arid3a). Using a combination of high-throughput miRNA profiling of the FoxD1(+)-derived cells and mRNA profiling of differentially expressed transcripts in FoxD1(GC);Dicer(fl/fl) kidneys, at least 72 miRNA:mRNA target interactions were identified to be suppressive of the apoptotic program. Together, the results support an indispensable role for stromal miRNAs in the regulation of apoptosis during kidney development.

| S-EPMC4632944 | biostudies-literature

Glomerular spatial transcriptomics of IgA nephropathy according to the presence of mesangial proliferation.

Project description:Mesangial proliferation is a diagnostic feature and a prognostic predictor of immunoglobulin A nephropathy (IgAN). We aimed to investigate the gene expression profiles of IgAN glomerulus according to the presence of mesangial proliferation. We performed spatial-specific transcriptomic profiling on kidney biopsy tissues using the GeoMx Digital Spatial Profiler. Twelve cases with three glomeruli for each case were profiled using direct pathologic classification (4 M1-IgAN, 4 M0-IgAN, and 4 donor controls). The results of enriched glom-specific genes demonstrated that M1-IgAN could be distinguished from controls (77 upregulated and 55 downregulated DEGs), while some DEGs were identified between M1-IgAN and M0-IgAN cases (24 upregulated and 8 downregulated DEGs) or between M0 and controls (1 upregulated and 16 downregulated DEGs). TCF21, an early podocyte damage marker, was the only differentially expressed gene (DEG) consistently upregulated in both M1-IgAN and M0-IgAN patients, whereas ATF3, EGR1, DUSP1, FOS, JUNB, KLF2, NR4A1, RHOB, and ZFP36 were consistently downregulated in IgAN cases. Glomeruli from M1-IgAN cases were significantly enriched for cell surface/adhesion molecules and gene expressions associated with vascular development or the extracellular matrix. Spatial transcriptomic analysis may contribute to dissecting structure-specific pathophysiology and molecular changes in IgAN.

| S-EPMC10817934 | biostudies-literature

A microRNA circuit mediates transforming growth factor-?1 autoregulation in renal glomerular mesangial cells.

Project description:Enhanced transforming growth factor-?1 (TGF-?1) expression in renal cells promotes fibrosis and hypertrophy during the progression of diabetic nephropathy. The TGF-?1 promoter is positively controlled by the E-box regulators, upstream stimulatory factors (USFs), in response to diabetic (high glucose) conditions; however, it is not clear whether TGF-?1 is autoregulated by itself. As changes in microRNAs (miRNAs) have been implicated in kidney disease, we tested their involvement in this process. TGF-?1 levels were found to be upregulated by microRNA-192 (miR-192) or miR-200b/c in mouse mesangial cells. Amounts of miR-200b/c were increased in glomeruli from type 1 (streptozotocin) and type 2 (db/db) diabetic mice, and in mouse mesangial cells treated with TGF-?1 in vitro. Levels of miR-200b/c were also upregulated by miR-192 in the mesangial cells, suggesting that miR-200b/c are downstream of miR-192. Activity of the TGF-?1 promoter was upregulated by TGF-?1 or miR-192, demonstrating that the miR-192-miR-200 cascade induces TGF-?1 expression. TGF-?1 increased the occupancy of activators USF1 and Tfe3, and decreased that of the repressor Zeb1 on the TGF-?1 promoter E-box binding sites. Inhibitors of miR-192 decreased the expression of miR-200b/c, Col1a2, Col4a1, and TGF-?1 in mouse mesangial cells, and in mouse kidney cortex. Thus, miRNA-regulated circuits may amplify TGF-?1 signaling, accelerating chronic fibrotic diseases such as diabetic nephropathy.

| S-EPMC3337779 | biostudies-literature

Sublytic C5b-9 induces glomerular mesangial cell proliferation via ERK1/2-dependent SOX9 phosphorylation and acetylation by enhancing Cyclin D1 in rat Thy-1 nephritis.

Project description:Glomerular mesangial cell (GMC) proliferation is a histopathological alteration in human mesangioproliferative glomerulonephritis (MsPGN) or in animal models of MsPGN, e.g., the rat Thy-1 nephritis (Thy-1N) model. Although sublytic C5b-9 assembly on the GMC membrane can trigger cell proliferation, the mechanisms are still undefined. We found that sublytic C5b-9-induced rat GMC proliferation was driven by extracellular signal-regulated kinase 1/2 (ERK1/2), sry-related HMG-box 9 (SOX9), and Cyclin D1. Here, ERK1/2 phosphorylation was a result of the calcium influx-PKC-α-Raf-MEK1/2 axis activated by sublytic C5b-9, and Cyclin D1 gene transcription was enhanced by ERK1/2-dependent SOX9 binding to the Cyclin D1 promoter (-582 to -238 nt). In addition, ERK1/2 not only interacted with SOX9 in the cell nucleus to mediate its phosphorylation at serine residues 64 (a new site identified by mass spectrometry) and 181 (a known site), but also indirectly induced SOX9 acetylation by elevating the expression of general control non-repressed protein 5 (GCN5), which together resulted in Cyclin D1 synthesis and GMC proliferation. Moreover, our in vivo experiments confirmed that silencing these genes ameliorated the lesions of Thy-1N rats and reduced SOX9 phosphorylation, acetylation and Cyclin D1 expression. Furthermore, the renal tissue sections of MsPGN patients also showed higher phosphorylation or expression of ERK1/2, SOX9, and Cyclin D1. In summary, these findings suggest that sublytic C5b-9-induced GMC proliferation in rat Thy-1N requires SOX9 phosphorylation and acetylation via enhanced Cyclin D1 gene transcription, which may provide a new insight into human MsPGN pathogenesis.

| S-EPMC8102557 | biostudies-literature

MDM2 Contributes to High Glucose-Induced Glomerular Mesangial Cell Proliferation and Extracellular Matrix Accumulation via Notch1.

Project description:Murine double minute 2 (MDM2) is an E3-ubiquitin ligase critical for various biological functions. Previous data have revealed an indispensable role of MDM2 in kidney homeostasis. However, its role in glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) accumulation during hyperglycemia condition remains unclear. In our present study, we found that MDM2 protein level was significantly upregulated in high glucose-treated GMCs, while knocking down MDM2 by siRNA could attenuate high glucose-induced ECM accumulation and GMCs proliferation. Unexpectedly, Nutlin-3a, a MDM2-p53 interaction blocker, had no benefit in protecting diabetic mice from renal impairment in vivo and in alleviating high glucose-induced ECM accumulation in vitro. Intriguingly, we found that Notch1 signaling activation was obviously attenuated by MDM2 depletion in GMCs with high glucose exposure. However, Numb, a substrate of MDM2 which suppresses Notch1 signaling, was found not to be involved in the MDM2 and Notch1 association. Moreover, our findings demonstrated that MDM2 interacted with Notch1 intracellular domain (NICD1) independent of Numb and regulated the ubiquitination status of NICD1. Collectively, our data propose a pivotal role of MDM2 in high glucose-induced GMC proliferation and ECM accumulation, via modulating the activation of Notch1 signaling pathway in an ubiquitination-dependent way.

| S-EPMC5583188 | biostudies-literature

TSP-1 promotes glomerular mesangial cell proliferation and extracellular matrix secretion in Thy-1 nephritis rats.

Project description:The proliferation of glomerular mesangial cells (GMC) and secretion of the extracellular matrix (ECM) in rat with Thy-1 nephritis (Thy-1N) resembling human mesangioproliferative glomerulonephritis have been explored for many years; however, the molecular mechanisms of GMC proliferation and ECM production remain unclear. Our previous studies have demonstrated that the thrombospondin-1 (TSP-1) gene was involved in mediating rat GMC proliferation and ECM synthesis induced by sublytic C5b-9 in vitro. In the present study, the roles of the TSP-1 gene in GMC proliferation, ECM production, and urinary protein secretion in Thy-1N rats were determined by using TSP-1 small hairpin RNA, and the results revealed that silencing of the TSP-1 gene in rat renal tissues could diminish GMC proliferation (P < 0.01) and ECM secretion (P < 0.01) as well as urinary protein secretion (P < 0.05) in Thy-1N rats. Together, the current findings suggested that TSP-1 gene expression was required for GMC proliferation and ECM production in Thy-1N rats.

| S-EPMC3596719 | biostudies-literature

Comparison of the SUMO1 and ubiquitin conjugation pathways during the inhibition of proteasome activity with evidence of SUMO1 recycling.

Project description:To investigate potential interplay between the SUMO1 (small ubiquitin-related modifier-1) and ubiquitin pathways of post-translational protein modification, we examined aspects of their localization and conjugation status during proteasome inhibition. Our results indicate that these pathways converge upon the discrete sub-nuclear domains known as PML (promyelocytic leukaemia protein) NBs (nuclear bodies). Proteasome inhibition generated an increased number of PML bodies, without any obvious increase in size. Using a cell line that constitutively expresses an epitope-tagged version of SUMO1, which was incorporated into high-molecular-mass conjugates, we observed SUMO1 accumulating in clusters around a subset of the NBs. Nuclear ubiquitin was initially observed in numerous speckles and foci, which bore no relationship to PML NBs in the absence of proteasome inhibition. However, during proteasome inhibition, total ubiquitin-conjugated species increased in the cell, as judged by Western blotting. Concomitantly the number of nuclear ubiquitin clusters decreased, and were almost quantitatively associated with the PML NBs, co-localizing with the SUMO-conjugated pool. Proteasome inhibition depleted the pool of free SUMO1 in the cell. Reversal of proteasome inhibition in the presence or absence of protein synthesis demonstrated that free SUMO1 was regenerated from the conjugated pool. The results indicate that a significant fraction of the free SUMO1 pool could be accounted for by recycling from the conjugated pool and indeed it may be that, as for ubiquitin, SUMO1 needs to be removed from conjugated species prior to processing by the proteasome. Taken together with other recent reports on the proteasome and PML NBs, these results suggest that the PML NBs may play an important role in integrating these pathways.

| S-EPMC1316262 | biostudies-other

PTX3 in serum induces renal mesangial cell proliferation but has no effect on apoptosis.

Project description:The present study aimed to investigate the effect of pentraxin 3 (PTX3) on the regulation of proliferation and apoptosis in human glomerular mesangial cells (HMCs). Small interfering (si)RNA was designed and synthesized to inhibit the expression of endogenous PTX3, and the effects on the proliferation and apoptosis of HMCs were detected by flow cytometry and an MTT assay. Western blot analysis was used to detect the activation of mitogen-activated protein kinase (MAPK) proteins in HMCs with PTX3 knockdown. Three siRNAs targeting PTX3 were individually transfected into HMCs for 48 h, and reverse-transcription quantitative PCR demonstrated that the relative mRNA expression of PTX3 was significantly decreased in all groups by up to 79.62% of that in the control group (P<0.05). Following transfection with PTX3-siRNA, the viability of an HMC line was significantly decreased in comparison with that of a control group transfected with scrambled siRNA. However, PTX3-siRNA did not significantly effect early and late apoptotic cell populations in HMCs compared with those in the control. Endogenous PTX3 interference was found to significantly decrease p38 MAPK, extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase phosphorylation. In conclusion, silencing of PTX3, inhibited the proliferation of HMCs via MAPK pathways, but exerted no effect on the apoptosis of HMCs.

| S-EPMC5774436 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data