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Role of calcium/calmodulin-dependent kinase type IV in podocyte function in lupus nephritis

ABSTRACT: 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.camkiv−/− 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55768 | GEO | 2014/08/01

SECONDARY ACCESSION(S): PRJNA240963

REPOSITORIES: GEO

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Role of calcium/calmodulin-dependent kinase type IV in podocyte function in lupus nephritis

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.

2014-08-01 | E-GEOD-55768 | biostudies-arrayexpress

Transcription profiling of mouse Podocytes reveal use of FcRn to clear IgG from the glomerular basement membrane

Project description:The glomerular filtration barrier prevents large serum proteins from being lost into the urine. It is not known, however, why the filter does not routinely clog with large proteins that enter the glomerular basement membrane (GBM). Here we provide evidence that an active transport mechanism exists to remove immunoglobulins that accumulate at the filtration barrier. We found that FcRn, an IgG and albumin transport receptor, is expressed in podocytes and functions to internalize IgG from the GBM. Mice lacking FcRn accumulated IgG in the GBM as they aged and tracer studies showed delayed clearance of IgG from the kidneys of FcRn deficient mice. Supporting a role for this pathway in disease, saturating the clearance mechanism potentiated the pathogenicity of nephrotoxic sera. These studies support the idea that podocytes play an active role in removing proteins from the GBM and suggest that genetic or acquired impairment of the clearance machinery is likely to be a common mechanism promoting glomerular diseases. Experiment Overall Design: Total RNA for genechip analysis was derived from two sources: Experiment Overall Design: 1) Primary mouse podocytes isolated by FACS sorting of collagenase digested glomeruli Experiment Overall Design: 2) In vitro differentiated conditionally immortalized mouse podocyte cell line. Experiment Overall Design: After obtaining genechip data, the expression of various IgG and albumin receptors was queried in the genechip data and then confirmed by RT-PCR.

2008-06-11 | E-GEOD-10017 | biostudies-arrayexpress

Podocytes use FcRn to clear IgG from the glomerular basement membrane

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OASIS overexpression in murine podocyte cell line

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Glomerular podocyte RNA-seq data of the podocyte-specific Profilin1 deficient mice

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Podocyte-specific deletion of tubular sclerosis complex 2 causes focal segmental glomerular sclerosis and progressive renal failure

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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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Project description:Alport syndrome (AS) is a genetic defect involving mutations of collagen IV α3, α4 or α5 genes, resulting in distinctive clinical features: kidney disease, hearing loss and eye abnormalities. Podocytes are responsible of production and correct assembly of the collagen IV isoforms, however, specific alterations of podocyte phenotype are currently scarce. We here generated immortalised AS urine-derived podocyte from three different patients. AS podocytes expressed a typical podocyte signature when compared to normal urine-derived podocytes, with comparable expression of podocyte markers. Each AS cell line showed a collagen IV profile that reflected the typical patient mutation. Furthermore, by RNA-sequencing 348 genes were found differentially expressed in Alport podocytes. Gene Ontology analysis underlined enrichment in genes involved in cell motility, adhesion, survival and angiogenesis. In parallel, AS podocyte motility was reduced. In conclusion, our data clearly indicate that AS podocytes display altered features connected but distinct from the collagen alterations.

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PIK3CA inhibition in models of proliferative glomerulonephritis and lupus nephritis

Project description:Proliferative glomerulonephritis is a severe condition often leading to kidney failure. There is a significant lack of effective treatment for these disorders. Here, following the identification of a somatic PIK3CA gain-of-function mutation in podocytes of a patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing and spatial transcriptomics the crucial role played by this pathway for proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation and inflammation. Additionally, we show that alpelisib, a PI3Kα inhibitor, improves glomerular lesions and kidney function in different mouse models of proliferative glomerulonephritis and lupus nephritis by targeting podocytes. Surprisingly, we determined that pharmacological inhibition of PI3Kα affects B and T lymphocyte population in lupus nephritis mouse models with decrease in the production of proinflammatory cytokines, autoantibodies and glomerular complement deposition, which are all characteristic features of PI3K delta (PI3Kδ) inhibition, the primary PI3K isoform expressed in lymphocytes. Importantly, PI3Kα inhibition does not impact lymphocyte function under normal conditions. These findings were then confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3Kα in proliferative glomerulonephritis and show that in this condition, alpelisib acts on both podocytes and the immune system.

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