Role of GR in protection of podocyte
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA483493 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13376161_1.fastq.gz | Fastqsanger.gz | |||
| SRR13376161_2.fastq.gz | Fastqsanger.gz | |||
| SRR13376162_1.fastq.gz | Fastqsanger.gz | |||
| SRR13376162_2.fastq.gz | Fastqsanger.gz | |||
| SRR13376163_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Testican-2 is a podocyte-derived glycoprotein encoded by SPOCK2. Circulating levels of testican-2 are associated with less glomerulosclerosis and better kidney prognosis, but its biological function in the podocyte is unknown. Methods: We studied the protective effect of testican-2 on immortalized cultured human podocytes and in mice treated with adriamycin. We used immunoprecipitation-mass spectrometry to identify binding partners of testican-2 and Bio-Layer Interferometry to characterize these protein-protein interactions. Using global Spock2 knockout mice, we assessed the impact of testican-2 deficiency in models of podocyte injury and also tested whether exogenous testican-2 confers podocyte protection in these testican-2 deficient mice. Finally, we analyzed testican-2 expression in human kidney biopsy samples. Results: Testican-2 reduced reduces adriamycin-induced podocyte injury in cultured human podocytes and mice. Vitronectin is a strong binding partner for testican-2, and testican-2 inhibited inhibits the interaction between vitronectin and integrin αVβ3, an important effector of podocyte injury. Consistent with this, testican-2 administration reduced reduces activation of integrin β3 in injured podocytes. Further, Spock2 deficiency increased increases susceptibility to podocyte injury due to adriamcyin and streptozotocin induced diabetes, as determined by albuminuria, foot process effacement, nephrin expression and WT1-positive podocyte number. Importantly, exogenous testican-2 circulated circulates to the kidney, bound binds to vitronectin, reduced reduces vitronectin-integrin β3 interaction, and reduced reduces podocyte injury in Spock2 deficient mice. Finally, glomerular testican-2 expression was is reduced in human focal segmental glomerulosclerosis and diabetic kidney disease, but not tubulointerstitial nephropathy. Conclusions: These findings identify a potential mechanism for testican-2 mediated kidney protection and highlight an opportunity to therapeutically target the podocyte’s interaction with its extracellular matrix.
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Project description:Nephrotic syndrome (NS) occurs when the glomerular filtration barrier becomes excessively permeable leading to massive proteinuria. In childhood NS, dysregulation of the immune system has been implicated and increasing evidence points to the central role of podocytes in the pathogenesis. Children with NS are typically treated with an empiric course of glucocorticoid (Gc) therapy; a class of steroids that are activating ligands for the glucocorticoid receptor (GR) transcription factor. Although Gc-therapy has been the cornerstone of NS management for decades, the mechanism of action, and target cell, remain poorly understood. We tested the hypothesis that Gc acts directly on the podocyte to produce clinically useful effects without involvement of the immune system. In human podocytes, we demonstrated that the basic GR-signalling mechanism is intact and that Gc induced an increase in podocyte barrier function. To gain mechanistic insight we performed RNA microarray and ChIP-sequencing and identified Gc regulation of motility genes.
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Project description:Glucocorticoid receptor (GR) is a ligand dependent transcription factor that plays a central role in inflammation. Part of a complex cellular network, GR activity is further modulated via protein–protein interactions . The regulation of GR by 14-3-3 proteins has been previously reported, though with differing sites of phosphorylation identified and variable consequences assigned. Hence, we sought to examine this protein–protein interaction and, using phosphorylated GR peptides, biophysical studies and X-ray crystallography, we identified key residues within the ligand binding domain of GR, T524 and S617, whose phosphorylation results in recognition by 14-3-3. Investigation of the kinases responsible for phosphorylation of these sites assigned a key role for MINK1 and cell-based approaches confirmed the importance of these two GR phosphosites and MINK1 in GR–14-3-3 binding. Together our results provide a molecular-level insight into 14-3-3 regulation of GR and highlight both MINK1 and the GR–14-3-3 axis as potential targets for future therapeutic intervention.
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Project description:Kidney podocytes and their slit diaphragms contribute to prevent urinary protein loss. T cell from patients with systemic lupus erythematosus display increased expression of calcium/calmodulin kinase IV (CaMKIV). Here we evaluated the functional role of CaMKIV in lupus nephritis (LN) using kidney biopsy specimens and human podocyte cell line (AB8/13). We found that exposure of podocytes to IgG from LN patients resulted in entry of IgG into the cytoplasm. CaMKIV expression was found to be increased in podocytes of LN kidney biopsy specimens and exposure to IgG from LN patients. IgG entered podocytes using the FcRn receptor because when podocytes where treated with FcRn siRNA less IgG was found in the cytoplasm. The DNA microarray studies of podocytes exposed to LN IgG revealed that genes that are related to the activation of immune cells or podocyte damage were upregulated. These genes included CD86, CaMKIV, PTPN22, PDE5A, CD47 and MALT1. Interestingly, CD86 expression decreased after silencing CaMKIV in podocytes. Also, in situ hybridization experiments showed that the expression of CD86 was reduced in podocytes from MRL/lpr.camkivM-bM-^HM-^R/M-bM-^HM-^R mice. IgG from LN patients may enter podocytes through the FcRn and causes the upregulation of a distinct set of genes which may alter podocyte function. Upregulation of CaMKIV appears to precede that of genes known to be linked to podocyte damage such as CD86. These findings may indicate that inhibition of CaMKIV may prove of clinical use in patients with LN. IgG Purification Kits (Dojindo Molecular Technologies, Inc.) are used for isolation and purification of immunoglobulin G of healthy and normal individual according to the manufacturerM-bM-^@M-^Ys protocol. Flow through the column was used for non IgG binding samples. Cultured human podocytes with IgG purified from sera of normal individuals and LN patient for 24 hr were collected for RNA.
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Project description:<p>Chronic kidney disease (CKD) is a major health issue, with podocyte injury with senescence playing a central role in glomerulosclerosis. This study investigates the link between glycolysis-derived serine metabolism and podocyte injury with senescence, focusing on the role of phosphoglycerate kinase 1 (PGK1) in the regulation of L-serine synthesis and podocyte homeostasis. Using in vivo and in vitro models, we examined the effects of angiotensin II (Ang II)-induced metabolic dysregulation on serine metabolism and its impact on podocyte function. The results demonstrate that Ang II downregulates PGK1 expression through the transcription factor FOXA1, leading to reduced L-serine biosynthesis, mitochondrial dysfunction, and increased cellular senescence in podocytes. Supplementing with L-serine or enhancing PGK1 expression in podocytes alleviated these pathological changes, restored mitochondrial function, and reduced senescence-associated phenotypes in CKD mouse models. Moreover, PGK1 was found to interact with keratin, type II cytoskeletal 1 (KRT1), stabilizing the cytoskeletal integrity of podocytes. These findings identify a novel metabolic pathway linking glycolysis, serine metabolism, and podocyte injury with senescence, suggesting that targeting the PGK1-serine axis may offer therapeutic potential for slowing podocyte senescence and CKD progression.</p>
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Project description:The Glucocorticoid Receptor (GR) is a potent metabolic regulator and a major drug target. While GR was shown to play various important roles in circadian biology, its rhythmic genomic actions have never been studied. Here we mapped GR’s genome-wide chromatin occupancy in mouse livers throughout the day/night cycle. We show how GR partitions metabolic processes during fasting (cellular maintenance, gluconeogenesis) and feeding (lipid and amino acid metabolism) by time-dependent binding and target gene regulation. Highlighting the dominant role GR plays in synchronizing circadian pathways, we find that the majority of oscillating genes harbor GR binding sites and depend on GR for amplitude stability . Surprisingly, this rhythmic pattern is altered by exposure to high fat diet in a ligand-independent manner. We show how the remodeling of oscillatory gene expression and GR binding result from a concomitant increase with Stat5 co-occupancy in obese mice, and that loss of GR reduces circulating glucose and triglycerides differentially during feeding and fasting. Altogether, our findings highlight GR’s fundamental role in the rhythmic orchestration of hepatic metabolism.
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