Abstract 11006: Increased Phosphatase and Tensin Homolog Plays a Crucial Role in Endothelial Dysfunction in Mice with Renal Failure
Background - Endothelial dysfunction plays a role in the mechanisms leading to cardiovascular complications in patients with chronic kidney disease (CKD). Recently, we showed that endothelial dysfunction is caused by reduced endothelial nitric oxide synthase (eNOS) phosphorylation at Ser1177 in CKD mice. However, little is known regarding the mechanisms of reduction of eNOS phosphorylation in CKD. Phosphatase and tensin homolog (PTEN) is a protein phosphatase, which reduces Ser473 phosphorylation of Akt, one of the established upstream kinases for eNOS phosphorylation. The aim of this study was to examine the role of PTEN in endothelial dysfunction in CKD.
Methods and Results - We created a CKD model by performing 5/6 nephrectomy in wild-type (WT) mice, which increased serum creatinine levels 2-fold without changing blood pressure. Endothelium-dependent relaxation was impaired, and phosphorylation of eNOS and Akt were reduced, in the aortas of WT mice with CKD (WT+CKD). Immunohistostaining revealed that PTEN expression was increased in the endothelial cells of the aorta in WT+CKD mice. To investigate the causal relationship between PTEN induction and endothelial dysfunction, CKD was created in endothelial cell-specific PTEN knockout mice (EC-Pten+/-). Basal and CKD-induced increases in serum creatinine levels were similar between WT and EC-Pten+/- mice. CKD-induced deterioration of endothelium-dependent relaxation (Figure), and reduction of eNOS and Akt phosphorylation, were abolished in EC-Pten+/- mice.
Conclusions - PTEN plays a crucial role in CKD-induced endothelial dysfunction by inhibition of the Akt-eNOS pathway. Thus, inhibition of endothelial PTEN induction may be a therapeutic target for the prevention and treatment of endothelial dysfunction in CKD patients.
- © 2012 by American Heart Association, Inc.