Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes

McKimpson, Wendy M.; Chen, Yun; Irving, James A.; Zheng, Min; Weinberger, Jeremy; Tan, Wilson Lek Wen; Tiang, Zenia; Jagger, Alistair M.; Chua, Streamson C.; Pessin, Jeffrey E.; Foo, Roger; Lomas, David A.; Kitsis, Richard N.

doi:10.1016/j.devcel.2021.02.011

Cited by 8 publications

(17 citation statements)

References 85 publications

(110 reference statements)

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“…TIMP3 is a matrix metalloproteinase inhibiter and its deficiency is associated with renal interstitial inflammation and fibrosis [ 34 ]. Serpina1a is a serine protease inhibitor which has been shown to be downregulated in mice with diabetes [ 35 ]. Increased protease activity may lead to inflammation and tubular epithelial cell death in the UUO model.…”

Section: Discussionmentioning

confidence: 99%

KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction

et al. 2022

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Progression of virtually all forms of chronic kidney disease (CKD) is associated with activation of pro-inflammatory and pro-fibrotic signaling pathways. Despite extensive research, progress in identifying therapeutic targets to arrest or slow progression of CKD has been limited by incomplete understanding of basic mechanisms underlying renal inflammation and fibrosis in CKD. Recent studies have identified Kruppel-like transcription factors that have been shown to play critical roles in renal development, homeostasis, and response to injury. Although KLF11 deficiency has been shown to increase collagen production in vitro and tissue fibrosis in other organs, no previous study has linked KLF11 to the development of CKD. We sought to test the hypothesis that KLF11 deficiency promotes CKD through upregulation of pro-inflammatory and pro-fibrogenic signaling pathways in murine unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis. We found that KLF11-deficiency exacerbates renal injury in the UUO model through activation of the TGF-β/SMAD signaling pathway and through activation of several pro-inflammatory chemokine signaling pathways. Based on these considerations, we conclude that agents increase KLF11 expression may provide novel therapeutic targets to slow the progression of CKD.

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Section: Discussionmentioning

confidence: 99%

KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction

et al. 2022

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“…Apoptosis in type 2 diabetes is mediated both through the death receptor and mitochondrial pathways ( Liadis et al., 2007 ; Zhou et al., 2000 ). Although the precise signaling is incompletely understood, we recently described one relevant mechanism ( McKimpson et al., 2021 ).…”

Section: Before You Beginmentioning

confidence: 99%

“…The resulting information may be useful for mechanistic studies and assessment of the contribution of β-cell death to pathogenesis. For complete details on the use and execution of this protocol, please refer to McKimpson et al. (2021) .…”

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confidence: 99%

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Inducing and measuring apoptotic cell death in mouse pancreatic β-cells and in isolated islets

McKimpson

Kitsis

2022

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“…Cardinal tissues of the body impacted by heightened insulin resistance (IR) and diminished insulin secretion in T2D include the pancreas, liver, skeletal muscle, and adipose tissue [13]. Alterations in the pancreas with T2D include the deposition of β-amyloid [14], reduced β-cell mass and increased β-cell apoptosis [15], as well as decreased size, irregularities of morphology and increased fat content [16]. A salient manifestation of T2D is the compromised insulin-mediated glucose uptake predominantly by skeletal muscle and to a lesser extent by adipose tissue resulting in hyperglycemia [17].…”

Section: Introductionmentioning

confidence: 99%

Highly perturbed genes and hub genes associated with type 2 diabetes in different tissues of adult humans: A bioinformatics analytic workflow

Silva

Demmer

Jönsson

et al. 2022

Preprint

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Introduction: Type 2 diabetes (T2D) has a complex etiology which is not fully elucidated. Identification of gene perturbations and hub genes of T2D may assist in personalizing care. Objectives: We aimed to identify highly perturbed genes and hub genes associated with T2D in different tissues of adult humans via an extensive workflow. Methods: Workflow comprised five sequential steps: systematic review of NCBI GEO database; identification and classification of differentially expressed genes (DEG); identification of highly perturbed genes via meta-analysis; identification of hub genes via network analysis; downstream analyses. Three meta-analytic strategies: random effects model (REM); vote counting approach (VC); p-value combining approach (CA), were applied. Nodes having above average betweenness, closeness, and degree in the network were defined as hub genes. Downstream analyses included gene ontologies, Kyoto Encyclopedia of Genes and Genomes pathways, metabolomics, COVID-19 related genes, and Genotype-Tissue Expression profiles. Results: Analysis of 27 eligible microarrays identified 6284 DEG (4592 down-regulated and 1692 up-regulated) within four tissue types. Tissue-specific gene expression was significantly greater than tissue non-specific (shared) gene expression. Meta-analysis of DEG identified 49, 27, and 8 highly perturbed genes via REM, VC, and CA, respectively, producing a compiled set of 79 highly perturbed (41 down-regulated and 38 up-regulated) genes. The 28 hub genes comprised 13 up-regulated, 9 down-regulated, and 6 predicted genes. Downstream analyses identified enrichments of: shared genes with other diabetes phenotypes; insulin synthesis and action related pathways and metabolomics; mechanistic associations with apoptosis and immunity-related pathways, COVID-19 related gene sets; and cell types demonstrating over- and under-expression of marker genes of T2D. Conclusions: We identified highly perturbed genes and hub genes of T2D and revealed their associations with other diabetes phenotypes and COVID-19 as well as pathophysiological manifestations such as those related to insulin, immunity, and apoptosis. Broader utility of the proposed pipeline is envisaged.

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Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes

Cited by 8 publications

References 85 publications

KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction

KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction

Inducing and measuring apoptotic cell death in mouse pancreatic β-cells and in isolated islets

Highly perturbed genes and hub genes associated with type 2 diabetes in different tissues of adult humans: A bioinformatics analytic workflow

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