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

Hui Geng, Rongpei Lan, Prajjal K. Singha, Annette Gilchrist, Paul H. Weinreb, Shelia M. Violette, Joel M. Weinberg, Pothana Saikumar, Manjeri A. Venkatachalam

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1236-1249
Number of pages14
JournalAmerican Journal of Pathology
Volume181
Issue number4
DOIs
StatePublished - Oct 2012

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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