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Targeting Phospholipase D4 attenuates kidney fibrosis by modulating immune system and activating proteases

ABSTRACT: Phospholipase D4 (PLD4), a single pass transmembrane glycoprotein, is amongst the most highly upregulated genes in mice kidneys subjected to chronic progressive fibrosis1. Here we characterized the expression pattern of PLD4 and found it to be over expressed in the proximal and distal tubular epithelial cells of mice and human kidneys following fibrosis. Subcellularly, PLD4 was localized to the endoplasmic reticulum, golgi apparatus and mitochondria and was confirmed to interact with Calmegin, Lectin, Mannose Binding 2 and Suppressor of Lin-12-Like Protein 1. Mechanistically, we show that PLD4 facilitates fibrogenesis by modulating innate and adaptive immune system thereby promoting TGF-β signaling pathway. Moreover, PLD4 induces the expression of α1-antitrypsin protein (AAT, a serine protease inhibitor) that results in subsequent down-regulation of Neutrophil Elastase (NE), thereby leading to the accumulation of extracellular proteins and scar tissue formation. Genetic silencing of PLD4 protected mice from development of fibrosis initiated by either Folic acid (FA) treatment or unilateral ureteral obstruction (UUO). Furthermore, therapeutic targeting of PLD4 using specific siRNA also protected the mice from kidney fibrosis via the same mechanisms. These results suggest that inhibition of PLD4 is sufficient to activate protease-mediated degradation of extracellular matrix and reversal of fibrosis thereby highlighting new therapeutic strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE87212 | GEO | 2017/08/31

SECONDARY ACCESSION(S): PRJNA343890

REPOSITORIES: GEO

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Project description:Fibrosis is defined as an abnormal matrix remodeling and loss of tissue homeostasis due to excessive synthesis and accumulation of extracellular matrix proteins in tissues. At present, there is no effective therapy for organ fibrosis. Previous studies demonstrated that aged plasminogen activator inhibitor-1(PAI-1) knockout mice develop spontaneously cardiac-selective fibrosis without affecting any other organs including kidney. Therefore, the PAI-1 knockout model of cardiac fibrosis provides an excellent opportunity to find the igniter(s) of cardiac fibrosis and its status in unaffected organs. We hypothesized that differential expressions of profibrotic and antifibrotic genes in PAI-1 knockout hearts and unaffected organs lead to cardiac selective fibrosis. In order to address this prediction, we have used a genome-wide gene expression profiling of transcripts derived from aged PAI-1 knockout hearts and kidneys. The variations of global gene expression profiling were compared within four groups: wildtype heart vs. knockout heart; wildtype kidney vs. knockout kidney; knockout heart vs. knockout kidney and wildtype heart vs. wildtype kidney. Analysis of illumina-based microarray data revealed that several genes involved in different biological processes such as immune system processing, response to stress, cytokine signaling, cell proliferation, adhesion, migration, matrix organization and transcriptional regulation were affected in hearts and kidneys by the absence of PAI-1, a potent inhibitor of urokinase- and tissue-type plasminogen activator. Importantly, the expressions of a number of genes, involved in profibrotic pathways were upregulated or downregulated in PAI-1 knockout hearts compared to wildtype hearts and PAI-1 knockout kidneys. To our knowledge, this is the first comprehensive report on the influence of PAI-1 on global gene expression profiling in the heart and kidney and its implication in several biological processes including fibrogenesis. Total RNA was extracted from hearts and kidneys derived from three PAI-1 knockout (12- month old) and three wild-type mice (12-month old) using RNeasy Fibrous Tissue Mini Kit (Qiagen, Valencia, CA) following the manufacturer’s instructions. The quality of RNA (RNA Integrity, RIN) in all 12 samples (3 wildtype hearts; 3 PAI-1 KO hearts; 3 wildtype kidneys; and 3 PAI-1 KO kidneys) was checked using the bioanalyzer. We have used a genome-wide gene expression profiling of transcripts derived from aged PAI-1 knockout hearts and kidneys. The variations of global gene expression profiling were compared within four groups: wildtype heart vs. knockout heart; wildtype kidney vs. knockout kidney; knockout heart vs. knockout kidney and wildtype heart vs. wildtype kidney.

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Targeting Phospholipase D4 attenuates kidney fibrosis by modulating immune system and activating proteases

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