1. Lysophosphatidic acid increases proximal tubule cell secretion of profibrotic cytokines PDGF-B and CTGF through LPA2- and Gαq-mediated Rho and αvβ6 integrin-dependent activation of TGF-β.
- Author
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Geng H, Lan R, Singha PK, Gilchrist A, Weinreb PH, Violette SM, Weinberg JM, Saikumar P, and Venkatachalam MA
- Subjects
- Animals, Cell Nucleus drug effects, Cell Nucleus metabolism, Connective Tissue Growth Factor genetics, Connective Tissue Growth Factor metabolism, Cytokines genetics, Fibrosis, Gene Expression Regulation drug effects, Humans, Kidney Tubules, Proximal drug effects, Kidney Tubules, Proximal pathology, Lipids blood, Male, Mice, Proto-Oncogene Proteins c-sis genetics, Proto-Oncogene Proteins c-sis metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Regeneration drug effects, Reperfusion Injury metabolism, Reperfusion Injury pathology, Signal Transduction drug effects, Smad2 Protein metabolism, Time Factors, Transforming Growth Factor beta metabolism, Antigens, Neoplasm metabolism, Cytokines metabolism, GTP-Binding Protein alpha Subunits, Gq-G11 metabolism, Integrins metabolism, Kidney Tubules, Proximal metabolism, Lysophospholipids pharmacology, Receptors, Lysophosphatidic Acid metabolism, rho GTP-Binding Proteins metabolism
- Abstract
After ischemia-reperfusion injury (IRI), kidney tubules show activated transforming growth factor β (TGF-β) signaling and increased expression of profibrotic peptides, platelet-derived growth factor-B (PDGF-B) and connective tissue growth factor (CTGF). If tubule repair after IRI is incomplete, sustained paracrine activity of these peptides can activate interstitial fibroblast progenitors and cause fibrosis. We show that lysophosphatidic acid (LPA), a ubiquitous phospholipid that is increased at sites of injury and inflammation, signals through LPA2 receptors and Gαq proteins of cultured proximal tubule cells to transactivate latent TGF-β in a Rho/Rho-kinase and αvβ6 integrin-dependent manner. Active TGF-β peptide then initiates signaling to increase the production and secretion of PDGF-B and CTGF. In a rat model of IRI, increased TGF-β signaling that was initiated early during reperfusion did not subside during recovery, but progressively increased, causing tubulointerstitial fibrosis. This was accompanied by correspondingly increased LPA2 and β6 integrin proteins and elevated tubule expression of TGF-β1, together with PDGF-B and CTGF. Treatment with a pharmacological TGF-β type I receptor antagonist suppressed TGF-β signaling, decreased the expression of β6 integrin, PDGF-B, and CTGF, and ameliorated fibrosis. We suggest that LPA-initiated autocrine signaling is a potentially important mechanism that gives rise to paracrine profibrotic signaling in injured kidney tubule cells., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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