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Lysophosphatidic acid increases proximal tubule cell secretion of profibrotic cytokines PDGF-B and CTGF through LPA2- and Gq-mediated Rho and v6 integrin-dependent activation of TGF-

Geng, H;Lan, R;Singha, PK;Gilchrist, A;Weinreb, PH;Violette, SM;Weinberg, JM;Saikumar, P;Venkatachalam, MA;

After ischemia-reperfusion injury (IRI), kidney tubules show activated transforming growth factor (TGF-) 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 Gq proteins of cultured proximal tubule cells to transactivate latent TGF- in a Rho/Rho-kinase and v6 integrin-dependent manner. Active TGF- peptide then initiates signaling to increase the production and secretion of PDGF-B and CTGF. In a rat model of IRI, increased TGF- 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 6 integrin proteins and elevated tubule expression of TGF-1, together with PDGF-B and CTGF. Treatment with a pharmacological TGF- type I receptor antagonist suppressed TGF- signaling, decreased the expression of 6 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.