MyD88 deficiency in podocytes does not change the outcome in experimental glomerulonephritis.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE222625 | GEO | 2024/01/11
REPOSITORIES: GEO
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Project description:Podocytes, highly differentiated glomerular epithelial cells, are essential for the maintenance of glomerular filtration barrier. Podocyte dysfunction in podocytes is a major determinant of proteinuric kidney disease. By RNA sequencing analysis in ADR-treated podocytes with or without MYDGF overexpression, we observed the significant changes of genes important in regulating cell cycle in podocytes with ADR treatment.
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Project description:Podocyte histone deacetylases (HDAC) are essential in maintaining a normal glomerular filtration barrier by modulating podocyte quiescence. Podocyte-specific loss Hdac1 and 2 in mice results in severe proteinuria and sustained DNA damage, likely caused by epigenetic alterations and deficient DNA repair, that result in podocyte senescence. Through glomeruli isolation and RNA-seq profiling from the mutant mice, we demonstrated that senescent podocytes develop a senescence-associated secretory phenotype (SASP) that contribute to the loss of podocytes. The role of HDACs in senescence may provide important clues in our understanding of how podocytes are lost following injury.
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Project description:Glomerular podocytes are highly differentiated cells that are key components of the kidney filtration units. The podocyte cytoskeleton builds the basis for the dynamic podocyte cytoarchitecture and plays a central role for proper podocyte function. Recent studies implicate that immunosuppressive agents including the mTOR-inhibitor everolimus have a protective role directly on the stability of the podocyte cytoskeleton. To elucidate mechanisms underlying mTOR-inhibitor mediated cytoskeletal rearrangements, we carried out microarray gene expression studies to identify target genes and corresponding pathways in response to everolimus. We analyzed the effect of everolimus in a puromycin aminonucleoside experimental in vitro model of podocyte injury. Upon treatment with puromycin aminonucleoside, microarray analysis revealed gene clusters involving cytoskeletal-associated pathways, adhesion, migration and extracellular matrix composition to be affected. Everolimus is capable of protecting podocytes from injury, both on the transcriptome and protein level. Rescued genes included TUBB2B and DCDC2, both involved in microtubule structure formation in neuronal cells but not identified in podocytes so far. Confirming gene expression data, Western-blot analysis in cultured podocytes showed an increase of TUBB2B and DCDC2 protein after everolimus treatment, and immunohistochemistry in healthy control kidneys confirmed a podocyte-specific expression. Microtubule-inhibitor experiments led to a maldistribution of TUBB2B and DCDC2 as well as an aberrant reorganization of the actin cytoskeleton. Tubb2bbrdp/brdp mice showed a delay in glomerular podocyte and capillary development. Taken together, our study suggests that off-target, non-immune mediated effects of the mTOR-inhibitor everolimus on the podocyte cytoskeleton might involve regulation of microtubules, revealing a potential novel role of TUBB2B and DCDC2 in glomerular podocyte development We analyzed the effect of everolimus on gene expression in a puromycin aminonucleoside experimental in vitro model of podocyte injury using microarrays
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Project description:Calcimimetic agents allosterically increase the calcium (Ca2+) sensitivity of the calcium-sensing receptor (CaSR), which is expressed in the tubular system and to a lesser extent in podocytes. Activation of this receptor can reduce glomerular proteinuria and structural damage in proteinuric animal models. However, the precise role of the podocyte CaSR is still unclear. A CaSR knockdown in cultured murine podocytes and a podocyte-specific CaSR knockout in BALB/c mice were generated to study its role in proteinuria and kidney function. Podocyte CaSR knockdown abolished the calcimimetic R-568 mediated Ca2+-influx, disrupted the actin cytoskeleton, reduced cellular attachment and migration velocity. Adriamycin (ADR)-induced proteinuria enhanced glomerular CaSR expression in wild type mice. Albuminuria, podocyte foot process effacement, podocyte loss and glomerular sclerosis were significantly more pronounced in ADR-treated podocyte-specific CaSR knockout mice compared to wild type littermates. The co-treatment of WT mice with ADR and the calcimimetic cinacalcet reduced the proteinuria in WT, but not in podocyte specific CaSR knockout mice. In addition, four children with nephrotic syndrome, objecting glucocorticoid therapy, were treated with cinacalcet for 1 to 33 days. Proteinuria declined transiently by up to 96% and edema resolved. The activation of podocyte CaSR regulates key podocyte functions in vitro and reduces toxin induced proteinuria and glomerular damage in mice. Our findings suggest a potential novel role of CaSR signaling in control of glomerular disease. Proteomic samples: two backgrounds (CaSR Knockdown vs WT) two conditions (Treatment = 1µM R568 vs untreated control) two timepoints (24h and 48h) five replicates each 2 x 2 x 2 x 5 = 40 samples
2022-03-14 | PXD030416 | Pride
Project description:Glomerular podocytes are highly differentiated cells that are key components of the kidney filtration units. The podocyte cytoskeleton builds the basis for the dynamic podocyte cytoarchitecture and plays a central role for proper podocyte function. Recent studies implicate that immunosuppressive agents including the mTOR-inhibitor everolimus have a protective role directly on the stability of the podocyte cytoskeleton. To elucidate mechanisms underlying mTOR-inhibitor mediated cytoskeletal rearrangements, we carried out microarray gene expression studies to identify target genes and corresponding pathways in response to everolimus. We analyzed the effect of everolimus in a puromycin aminonucleoside experimental in vitro model of podocyte injury. Upon treatment with puromycin aminonucleoside, microarray analysis revealed gene clusters involving cytoskeletal-associated pathways, adhesion, migration and extracellular matrix composition to be affected. Everolimus is capable of protecting podocytes from injury, both on the transcriptome and protein level. Rescued genes included TUBB2B and DCDC2, both involved in microtubule structure formation in neuronal cells but not identified in podocytes so far. Confirming gene expression data, Western-blot analysis in cultured podocytes showed an increase of TUBB2B and DCDC2 protein after everolimus treatment, and immunohistochemistry in healthy control kidneys confirmed a podocyte-specific expression. Microtubule-inhibitor experiments led to a maldistribution of TUBB2B and DCDC2 as well as an aberrant reorganization of the actin cytoskeleton. Tubb2bbrdp/brdp mice showed a delay in glomerular podocyte and capillary development. Taken together, our study suggests that off-target, non-immune mediated effects of the mTOR-inhibitor everolimus on the podocyte cytoskeleton might involve regulation of microtubules, revealing a potential novel role of TUBB2B and DCDC2 in glomerular podocyte development
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Project description:Podocytes are terminally differentiated cells at the kidney filtration barrier and exposed to considerable mechanical strain. Podocyte injury causes morphological changes as a result of cytoskeletal reorganizations and failure of the filtration barrier. The transcriptional co-activators YAP/TAZ are tightly controlled through hippo signaling and responsive to mechanical cues. Here, we show that YAP is upregulated upon podocyte injury to activate YAP-dependent target genes. This activation preceded the development of proteinuria. In contrast, similar perturbations of cells in culture did not reveal increased YAP activity but showed a downregulation of YAP/TAZ activity when cells were grown on stiff surface. However, culture of cells on soft matrix or inhibition of stress fiber formation allowed recapitulation of the damage-induced YAP upregulation indicating a mechanotransduction-dependent mechanism of YAP over-activity. Interestingly, increased expression of YAP targets was confirmed in renal biopsies from patients with glomerular disease. Consistently, pharmacological inhibition of YAP/TEAD activity ameliorated glomerular disease in vivo. These data suggest that perturbation of the mechanosensitive hippo signaling pathway may be a therapeutic principle in podocyte disease.
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Project description:Podocytes are the highly specialised cells within the glomeruli of the kidney that maintain the filtration barrier by forming interdigitating foot processes and slit-diaphragms. Disruption to these features result in proteinuria. Studies into podocyte biology and disease has been hampered by a paucity of in vitro models of this non-proliferative cell type. Here we characterise sieved glomeruli from kidney organoids derived from human pluripotent stem cells. Compared to conditionally immortalised podocytes, organoid-derived glomeruli show superior podocyte-specific gene and protein expression, morphology and functional properties. Using CRISPR-derived MAFB reporter iPSC lines, homozygous MAFB mutant organoids recapitulated the anticipated disease related transcriptional changes. Culture of kidney organoids on chicken chorioallantoic membrane resulted in glomerular vascularisation, glomerular filtration barrier assembly, formation of slit diaphragms and fenestrated endothelial cells. This definitively demonstrates that human iPSC kidney organoid-derived glomeruli can serve as an accurate model of human podocytopathies and glomerular disease in vitro.
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Project description:Podocytes are highly specialised cells within the glomeruli of the kidney that maintain the filtration barrier by forming interdigitating foot processes and slit-diaphragms. Disruption to these features result in proteinuria and glomerulosclerosis. Studies into podocyte biology and disease have previously relied on conditionally immortalised cell lines due to the non- proliferative nature of this cell type. Here we describe an advanced model to study both podocyte and glomerular biology using isolated glomeruli from kidney organoids derived from human pluripotent stem cells.
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Project description:Podocytes play an important filtration role in the kidney. We examined culture condition for efficient podocyte induction and established a method to selectively induce podocytes from human iPS cells. To understand how expression profiles of human iPS cell-derived podocytes were close to that in vivo, we isolated human adult podocytes for human adult kidney. Purified RNAs from human iPS cells, nephron progenitor cells, human immortalized podocyte cell line, human iPS cell-derived podocytes, and sorted human adult podocytes were analyzed by RNA-seq.
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