749 COMPLEMENT 3 ACTIVATES THE RENAL RENIN-ANGIOTENSIN SYSTEM BY THE EPITHELIAL-TO-MESENCHYMAL TRANSITION

Abstract

Objective: Recent studies have suggested that complement 3 (C3) excerts the pleiotrophic effects to maintain the stemness and the synthetic phenotype of mesenchymal cells. We have demonstrated that mesenchymal cells such as VSMCs and mesangial cells from SHR genetically produce C3. Mature tubular epithelial cells in adult kidney canundergo epithelial-to-mesenchymal transition (EMT), a phenotypicconversion that is fundamentally linked to the pathogenesisof renal interstitial fibrosis. We investigated role of C3 in EMT phenomena and the renal renin-angiotensin (RA) systems. Methods: Mice TCMK-1 epithelial cells were incubated with C3a in vitro. We induced EMT by UUO in wild type B6 or C3 KO mice. EMT was evaluated by decreases in E-cadherin and increases in α-SMA of h-caldesmon.The expression for C3 and renin was examined by immunocytochemistry, Western Blot and real time PCR. Expressions for C3, renin, LXRα and rorenin receptor were evaluated by immunohistochemistry and real time PCR. Results: C3a induced EMT and in TCMK-1 cells in which renin was expressed with nuclear localization of LXRα. In wild type mice, C3 and renin were strongly stained in the degenerated nephrotubulus at same localization with increases in expression of LXRα and rorenin receptor. In C3 KO mice, the EMT phenomen was suppressed with no expression of renin and C3. Conclusion: C3 induce the EMT to dedifferentiate the epithelial cells that produce renin through the induction of LXRα in kidney. C3 may be a primary factor to activate the renal RA systems to induce hypertension.