Targeting Phospholipase D4 Attenuates Kidney Fibrosis

Trivedi, P.P.; Kumar, Ramya; Iyer, Ashwin; Boswell, Sarah A.; Gerarduzzi, Casimiro; Dadhania, Vivekkumar P.; Herbert, Zach; Joshi, Nikita; Luyendyk, James P.; Humphreys, Benjamin D.; Vaidya, Vishal S.

doi:10.1681/asn.2016111222

Cited by 24 publications

(19 citation statements)

References 55 publications

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“…First, PLD2 , a family member gene of PLD4 , is a susceptibility gene to SLE in the European population 11. Second, PLD4 regulates kidney fibrosis in human and mice,25 which is a severe complication of SLE. Third, Pld4 is dominantly expressed in immune-related organs and cells including B cells, monocytes and dendritic cells 26.…”

Section: Resultsmentioning

confidence: 99%

PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes

et al. 2019

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ObjectivesSystemic lupus erythematosus (SLE) is an autoimmune disease that is characterised by autoantibody production and widespread inflammation damaging many organs. Previous genome-wide association studies (GWASs) have revealed over 80 genetic determinants of SLE, but they collectively explain a fraction of the heritability, and only a few were proven in vivo for the involvement in SLE. We conducted a meta-analysis of SLE GWAS in the Japanese population, followed by functional analyses of a susceptibility gene with use of mutant mice.MethodsWe conducted a meta-analysis of two GWASs comprising a total of 1363 cases and 5536 controls using the 1000 Genome Project data as an imputation reference. Enrichment analyses for functional annotations were conducted. We examined Phospholipase D4 (Pld4) mutant mice to assess functional involvement of a genetic determinant.ResultsWe found a total of 14 significant loci, which included rs2582511 in AHNAK2/PLD4 recently reported in a Chinese study and a novel locus of rs143181706 in MAMLD1 (p=7.9×10−11 and 3.7×10–8, respectively). PLD4 risk allele was associated with anti-dsDNA antibody production. Enrichment analysis of genetic signals revealed involvement of a wide range of immune-related cells and pathways. Pld4 mutant mice revealed remarkably low body weight. The mice demonstrated autoimmune phenotypes compatible with SLE, including splenomegaly and lymphadenopathy, expansion of B cells and hypersecretion of BAFF and production of autoantibodies especially anti-nuclear antibody and anti-dsDNA antibody.Conclusions We found a novel susceptibility gene to SLE. Pld4 mutant mice revealed autoimmune phenotypes suggesting functional involvement of PLD4 with the basics of SLE.

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Section: Resultsmentioning

confidence: 99%

PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes

et al. 2019

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“…In addition to PLD1 and PLD2, a novel role for PLD4 in the development of kidney fibrosis has been reported. Genetic deletion of PLD4, a transmembrane glycoprotein and an isoform of PLD that lacks any enzyme activity, in kidney tubular epithelial cells attenuated development of kidney fibrosis [243]; however, the mechanism of protection in the absence of PA generation is unknown.…”

Section: Phospholipase D/phosphatidic Acid Signaling Axis In Developmmentioning

confidence: 99%

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

Suryadevara

Ramchandran

Kamp

et al. 2020

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. The molecular mechanisms involved in the pathophysiology of IPF are incompletely defined. Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells have been implicated in the development and progression of fibrosis. Regardless of the cell types involved, changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis. Lipid mediators derived from phospholipids, sphingolipids, and polyunsaturated fatty acids play an important role in the pathogenesis of pulmonary fibrosis and have been described to exhibit pro- and anti-fibrotic effects in IPF and in preclinical animal models of lung fibrosis. This review describes the current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipids and their metabolizing enzymes in the development of lung fibrosis. Further, several of the lipid mediators and enzymes involved in their metabolism are therapeutic targets for drug development to treat IPF.

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“…In large stones, the relative increased levels of coagulation factors, protease inhibitors, and SOD1 suggest that injury and inflammation may be a normal part of stone formation. Hydrogen peroxide also reacts with free cysteine to form the oxidized dimer cystine, reportedly leading to kidney stone formation [35]. Interestingly, we found SOD1, which generates H 2 O 2 from superoxide, at higher relative abundances in large stones.…”

Section: Discussionmentioning

confidence: 68%

Comprehensive Proteomic Quantification of Bladder Stone Progression in a Cystinuric Mouse Model Using Data-Independent Acquisitions

Rose

Basisty²,

Zee³

et al. 2021

Preprint

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Cystinuria is one of various disorders that cause biomineralization in the urinary system, including bladder stone formation in humans. It is most prevalent in children and adolescents and more aggressive in males. There is no cure, and only limited disease management techniques help to solubilize the stones. Recurrence, even after treatment, occurs frequently. Other than a buildup of cystine, little is known about factors involved in the formation, expansion, and recurrence of these stones. This study sought to define the growth of bladder stones, guided by micro-computed tomography imaging, and to profile dynamic stone proteome changes in a cystinuria mouse model. After bladder stones developed in vivo, they were harvested and separated into four developmental stages (sand, small, medium and large stone), based on their size. Data-dependent and data-independent acquisitions allowed deep profiling of stone proteomics. The proteomic signatures and pathways illustrated major changes as the stones grew. Stones initiate from a small nidus, grow outward, and show major enrichment in ribosomal proteins and factors related to coagulation and platelet degranulation, suggesting a major dysregulation in specific pathways that can be targeted for new therapeutic options.

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Targeting Phospholipase D4 Attenuates Kidney Fibrosis

Cited by 24 publications

References 55 publications

PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes

PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

Comprehensive Proteomic Quantification of Bladder Stone Progression in a Cystinuric Mouse Model Using Data-Independent Acquisitions

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