Lupus Nephritis IgG Induction of Calcium/Calmodulin‐Dependent Protein Kinase IV Expression in Podocytes and Alteration of Their Function

Ichinose, Kunihiro; Ushigusa, Takeshi; Nishino, Ayako; Nakashima, Yosikazu; Suzuki, Takahisa; Horai, Yoshiro; Koga, Tomohiro; Kawashiri, Shin‐ya; Iwamoto, Naoki; Tamai, Mami; Arima, Kei; Nakamura, Hideki; Obata, Yoko; Yamamoto, Kazuo; Origuchi, Tomoki; Nishino, Tomoya; Kawakami, Atsushi; Tsokos, George C.

doi:10.1002/art.39499

Cited by 54 publications

(38 citation statements)

References 38 publications

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“…One plausible mechanism is that these IgG molecules enter podocytes via neonatal Fc receptor (FcRn). This mechanism is supported by the recent observation that IgG from lupus patients entered podocytes via the FcRn receptor and up-regulated Ca 21 /calmodulindependent protein kinase IV, which was followed by increased expression of genes related to podocyte damage and T cell activation (36). It should be clear that other mechanisms are plausible.…”

Section: Discussionmentioning

confidence: 73%

Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis

Guo

Wang

et al. 2017

Arthritis & Rheumatology

161

107

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Objective Development of proteinuria in lupus nephritis (LN) is associated with podocyte dysfunction. The NLRP3 inflammasome has been implicated in the pathogenesis of LN. This study investigates whether NLRP3 inflammasome activation is involved in the development of podocyte injury in LN. Methods A fluorescence-labeled caspase-1 inhibitor probe was used to detect the activation of NLRP3 inflammasomes in podocytes in lupus-prone NZM2328 mice and in renal biopsies from LN patients. MCC950, a selective inhibitor of NLRP3, was used to treat NZM2328 mice. Proteinuria, ultrastructure of podocytes and renal pathology were evaluated. In vitro, sera from diseased NZM2328 mice were used to stimulate a podocyte cell line and cells were subjected to flow cytometry analysis. Results NLRP3 inflammasomes were activated in podocytes of lupus-prone mice and LN patients. Inhibition of NLRP3 with MCC950 ameliorated proteinuria, renal histological lesions and podocyte foot process effacement in lupus-prone mice. In vitro, sera from NZM2328 diseased mice activated NLRP3 inflammasomes in the podocyte cell line through reactive oxygen species (ROS) production. Conclusion NLRP3 inflammasomes were activated in podocytes of both LN patients and in lupus-prone mice. Activation of NLRP3 is involved in the pathogenesis of podocyte injuries and the development of proteinuria in LN.

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Section: Discussionmentioning

confidence: 73%

Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis

Guo

Wang

et al. 2017

Arthritis & Rheumatology

161

107

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“…Pharmacologic inhibition (12) or genetic deletion of CaMK4 (13) and targeted delivery of a CaMK4 inhibitor to CD4 + T cells (14) effectively prevented LN in the lupus-prone MRL.lpr mouse. We have found that CaMK4 was increased and colocalized with nephrin in the glomeruli of SLE patients and that IgG from LN patients upregulated CaMK4 in podocyte cultures (15).…”

Section: Introductionmentioning

confidence: 74%

CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease

Maeda¹,

Otomo²,

Yoshida³

et al. 2018

Journal of Clinical Investigation

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Podocyte malfunction occurs in autoimmune and nonautoimmune kidney disease. Calcium signaling is essential for podocyte injury, but the role of Ca2+/calmodulin-dependent kinase (CaMK) signaling in podocytes has not been fully explored. We report that podocytes from patients with lupus nephritis and focal segmental glomerulosclerosis and lupus-prone and lipopolysaccharide- or adriamycin-treated mice display increased expression of CaMK IV (CaMK4), but not CaMK2. Mechanistically, CaMK4 modulated podocyte motility by altering the expression of the GTPases Rac1 and RhoA and suppressed the expression of nephrin, synaptopodin, and actin fibers in podocytes. In addition, it phosphorylated the scaffold protein 14-3-3β, which resulted in the release and degradation of synaptopodin. Targeted delivery of a CaMK4 inhibitor to podocytes preserved their ultrastructure, averted immune complex deposition and crescent formation, and suppressed proteinuria in lupus-prone mice and proteinuria in mice exposed to lipopolysaccharide-induced podocyte injury by preserving nephrin/synaptopodin expression. In animals exposed to adriamycin, podocyte-specific delivery of a CaMK4 inhibitor prevented and reversed podocyte injury and renal disease. We conclude that CaMK4 is pivotal in immune and nonimmune podocyte injury and that its targeted cell-specific inhibition preserves podocyte structure and function and should have therapeutic value in lupus nephritis and podocytopathies, including focal segmental glomerulosclerosis.

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“…Recently, Haddon et al [43] demonstrated that pediatric SLE patients with kidney involvement possessed a different autoantibody profile than those without kidney involvement. Other groups then showed differences in expression levels of RNA and microRNAs in lupus nephritis biopsies [44, 45], suggesting that different clinical phenotypes may have individualized gene expression signatures.…”

Section: Discussionmentioning

confidence: 99%

Chromatin landscapes and genetic risk in systemic lupus

et al. 2016

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BackgroundSystemic lupus erythematosus (SLE) is a multi-system, complex disease in which the environment interacts with inherited genes to produce broad phenotypes with inter-individual variability. Of 46 single nucleotide polymorphisms (SNPs) shown to confer genetic risk for SLE in recent genome-wide association studies, 30 lie within noncoding regions of the human genome. We therefore sought to identify and describe the functional elements (aside from genes) located within these regions of interest.MethodsWe used chromatin immunoprecipitation followed by sequencing to identify epigenetic marks associated with enhancer function in adult neutrophils to determine whether enhancer-associated histone marks were enriched within the linkage disequilibrium (LD) blocks encompassing the 46 SNPs of interest. We also interrogated available data in Roadmap Epigenomics for CD4+ T cells and CD19+ B cells to identify these same elements in lymphoid cells.ResultsAll three cell types demonstrated enrichment of enhancer-associated histone marks compared with genomic background within LD blocks encoded by SLE-associated SNPs. In addition, within the promoter regions of these LD blocks, all three cell types demonstrated enrichment for transcription factor binding sites above genomic background. In CD19+ B cells, all but one of the LD blocks of interest were also enriched for enhancer-associated histone marks.ConclusionsMuch of the genetic risk for SLE lies within or near genomic regions of disease-relevant cells that are enriched for epigenetic marks associated with enhancer function. Elucidating the specific roles of these noncoding elements within these cell-type-specific genomes will be crucial to our understanding of SLE pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1169-9) contains supplementary material, which is available to authorized users.

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Lupus Nephritis IgG Induction of Calcium/Calmodulin‐Dependent Protein Kinase IV Expression in Podocytes and Alteration of Their Function

Cited by 54 publications

References 38 publications

Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis

Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis

CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease

Chromatin landscapes and genetic risk in systemic lupus

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