GENE THERAPY OD ACUTE RENAL FAILURE BY CELL CYCLE-REGULATED GENES

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We investigated the genes which play important roles in the regeneration of renal tubules during renal failure. Wnt-4 is known to be expressed in the mesonephric duct in embryonic development. It is tempting to speculate that the Wnt-4-β-catenin pathway contributes to the recovery from acute renal failure (ARF). In this study we used an in vivo model of ARF rats to clarify the significance of the Wnt-4-β-catenin pathway in ARF. ARF was induced by clamping the rat left renal artery for 1h. At 3, 6, 12, 24, 48, and 72 h after reperfusion, we extracted whole kidney homogenate and total RNA for examination by Western blot analysis and real-time RT-PCR. Wnt-4 mRNAand protein expression were strongly increased at 3-12 h and 6-24 h after ischemia, respectively. In immunohistological examination, Wnt-4 was expressed in the proximal tubules and co- expressed with aquaporin-1, GM130, and PCNA Cyclin Dl and cyclin A were expressed at 24-48 h after reperfusion. In addition, the overexpression of Wnt-4 and β- catenin promoted the cell cycle and increased the promoter activity and protein expression of cyclin Dl in LLC-PK1 cells. Taken together, these data suggest that the Wnt-4-β-catenin pathway plays a key role in the cell cycle progression of renal tubules in ARF. The Wnt-4-β-catenin pathway may regulate the transcription of cyclin Dl and control the regeneration of renal tubules in ARF.