3553 TUBULE CELL-DERIVED ANGIOPOIETIN-2 EXACERBATES INFLAMMATION AND IS DETRIMENTAL TO RENAL FIBROSIS

Abstract Background and Aims Our previous studies have shown that angiogenic growth factors are dysregulated in fibrotic kidneys. In murine models of progressive renal disease, angiopoietin-2 (Angpt2) was upregulated in injured tubule epithelial cells. We hypothesize that overexpression of Angpt2 in tubule epithelial cells would exacerbate renal fibrosis and inflammation. Method The unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI) are used as the murine model of chronic kidney disease. We use the tetracycline/doxycycline-controlled Tet-on system to induce tubule cell-specific overexpression of Angpt2 before the induction of renal fibrosis. Transgenic mice carrying both Pax8-rtTA and pTetos-hAngpt2 genes (double transgenic mice) are used for Angpt2 overexpression. Littermates that inherit single or no transgene serve as experimental controls. Doxycycline is administered to adult (8 weeks) mice to overexpress Angpt2 in tubule epithelial cells. Results Doxycycline administration induce overexpression of human Anpgt2 in the tubule epithelial cells of both sham and fibrotic kidneys. Compared to littermate controls after the UUO and UIRI surgery, the expression of fibrosis-related genes, Col1a1, Col3a1, and Acta2 are higher in the kidneys of double transgenic mice. Deposition of picrosirius red-stained collagen fibrils is significantly higher in double transgenic mice. Inflammatory cell infiltration is also significantly higher in double transgenic mice. Conclusion Overall, these findings suggest that increased Angpt2 in tubule epithelial cells deteriorate renal fibrosis through detrimental inflammation. Further studies are necessary to explore the participating cellular components and pathogenic mechanisms.