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Publication : Targeting Phospholipase D4 Attenuates Kidney Fibrosis.

First Author  Trivedi P Year  2017
Journal  J Am Soc Nephrol Volume  28
Issue  12 Pages  3579-3589
PubMed ID  28814511 Mgi Jnum  J:292997
Mgi Id  MGI:6435833 Doi  10.1681/ASN.2016111222
Citation  Trivedi P, et al. (2017) Targeting Phospholipase D4 Attenuates Kidney Fibrosis. J Am Soc Nephrol 28(12):3579-3589
abstractText  Phospholipase D4 (PLD4), a single-pass transmembrane glycoprotein, is among the most highly upregulated genes in murine kidneys subjected to chronic progressive fibrosis, but the function of PLD4 in this process is unknown. Here, we found PLD4 to be overexpressed in the proximal and distal tubular epithelial cells of murine and human kidneys after fibrosis. Genetic silencing of PLD4, either globally or conditionally in proximal tubular epithelial cells, protected mice from the development of fibrosis. Mechanistically, global knockout of PLD4 modulated innate and adaptive immune responses and attenuated the upregulation of the TGF-beta signaling pathway and alpha1-antitrypsin protein (a serine protease inhibitor) expression and downregulation of neutrophil elastase (NE) expression induced by obstructive injury. In vitro, treatment with NE attenuated TGF-beta-induced accumulation of fibrotic markers. Furthermore, therapeutic targeting of PLD4 using specific siRNA protected mice from folic acid-induced kidney fibrosis and inhibited the increase in TGF-beta signaling, decrease in NE expression, and upregulation of mitogen-activated protein kinase signaling. Immunoprecipitation/mass spectrometry and coimmunoprecipitation experiments confirmed that PLD4 binds three proteins that interact with neurotrophic receptor tyrosine kinase 1, a receptor also known as TrkA that upregulates mitogen-activated protein kinase. PLD4 inhibition also prevented the folic acid-induced upregulation of this receptor in mouse kidneys. These results suggest inhibition of PLD4 as a novel therapeutic strategy to activate protease-mediated degradation of extracellular matrix and reverse fibrosis.
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