Deletion of Promotes Kidney Fibrosis in a Murine Model of Unilateral Ureteral Obstruction.

We investigated the role of Akt1, one of the three isoforms of Akt, in renal fibrosis using the murine model of unilateral ureteral obstruction (UUO). We subjected wild type and mice to UUO. The Akt1 gene was silenced in vitro using short hairpin RNA delivered via a lentiviral vector in human proximal tubular cells (HK2 cells) and kidney fibroblasts (NRK-49F cells). The obstructive kidneys of mice showed more severe tubulointerstitial fibrosis than those of wild type mice. The expression of fibronectin and type I collagen was significantly increased in obstructed kidneys of mice compared to those of wild type mice. The important finding was that the expression of transforming growth factor 1 (TGF1) was significantly increased in the mice compared to the wild type mice. The knockdown of enhanced the expression of TGF1 in HK2 cells. Interestingly, the upregulation of TGF1 due to genetic knockdown of was associated with activation of signal transducer and activator of transcript 3 (STAT3) independently of the Smad pathway in NRK-49F and HK2 cells. Immunohistochemical staining also showed that expression of phosphorylated STAT3 was more increased in mice than in wild type mice after UUO. Additionally, the deletion of led to apoptosis of the renal tubular cells in both in vivo and in vitro studies. Conclusively, these results suggest that the deletion of may contribute to renal fibrosis via induction of the TGF1/STAT3 pathway in a murine model of UUO.