부산대학교 도서관

Lysophosphatidic acid (LPA) increases PDGFB and CTGF production and secretion by proximal tubule (PT) cells through LPA2-receptor-Gαq-αvβ6-integrin mediated activation of TGFB1. LPA2, β6-integrin, PDGFB, and CTGF increase in kidneys after ischemia reperfusion injury (IRI), coinciding with fibrosis. TGFB1-receptor antagonist SD-208 prevents increases of β6-integrin, TGFB1-SMAD signaling and PDGFB/CTGF expression after IRI, and ameliorates fibrosis (Am J Pathol 174:1291, 2009; Am J Pathol 181:1236, 2012). We report now that LPA1-receptor signaling through EGFR-ERK1/2-AP-1 co-operates with LPA2-dependent TGFB1 signaling to additively increase PDGFB/CTGF production and secretion by PT cells. Conversely, inhibition of both pathways results in greater suppression of PDGFB/CTGF production and secretion, and promotes greater PT cellular differentiation than inhibiting one pathway alone. Antagonism of LPA-generating enzyme autotaxin suppressed signaling through both pathways. After IRI, kidneys showed not only more LPA2, nuclear SMAD2/3 and PDGFB/CTGF, but also increased LPA1 and autotaxin proteins, together with enhanced EGFR/ERK1/2 activation. Remarkably, TGFB1 receptor antagonist SD-208 prevented all of these abnormalities excepting increased LPA2. SD208 inhibits only one arm of LPA signaling: LPA2-Gαq-αvβ6-integrin dependent production of active TGFB1 and its receptor-bound downstream effects. Consequently, far-reaching protection by SD-208 against IRI-induced signaling alterations and tubule-interstitial pathology is not fully explained by our data. TGFB1 dependent feed forward modulation of LPA1 signaling is one possibility. SD208 effects may also involve mitigation of injury caused by IRI-induced TGFB1 signaling in endothelial cells and monocytes. Our results have translational implications for using TGFB1 receptor antagonists, LPA1 and LPA2 inhibitors concurrently, and autotaxin inhibitors in AKI to prevent CKD development.