MPS 01-08 CYCLIC GMP DEPENDENT PROTEIN KINASE-AKT PATHWAY IS ESSENTIAL FOR COMPENSATORY RENAL HYPERTROPHY AND MAINTENANCE RENAL FUNCTION AFTER UNILATERAL NEPHRECTOMY

Objective: Renal hypertrophy as an early compensatory mechanism to replace the loss of functioning tissue ultimately turns into a maladaptive process leading to progressive deterioration of renal function. We previously reported that nitric oxide (NO) production in the kidney is increased in the early phase after nephrectomy. However, the precise mechanism of increased NO production and its role in compensatory renal hypertrophy following nephrectomy remain unclear. We therefore hypothesize that the eNOS-soluble guanylate cyclase (sGC)-protein kinase G (PKG) pathway plays a crucial role in compensatory renal hypertrophy following unilateral nephrectomy. Design and Method: We used the following three groups of mice (male; background: C57BL6;): wild-type (WT), eNOS knockout (eNOS-KO) and endothelial specific eNOS transgenic (ECeNOS-TG) mice. These mice underwent left unilateral nephrectomy (i.e., WT-Nx, eNOS-KO-Nx and ECeNOS-TG-Nx), and their right kidney and serum were obtained for examination 2 weeks after nephrectomy. Next, we investigated the mechanism of NO-induced hypertrophy in vitro using human proximal tubular epithelial cells (hPTECs). hPTECs were stimulated with sGC stimulator BAY 41-2272 (Bay), and the activity of PKG and the downstream pathway were examined. In addition, we examined the effects of BAY in vivo by treating eNOS-KO mice with BAY (eNOS-KO-Nx-BAY) after unilateral nephrectomy. Results: Two weeks after nephrectomy, compensatory renal hypertrophy was markedly suppressed in the eNOS-KO-Nx group compared with the WT-Nx group. And serum CRN was increased in eNOSKO mice after nephrectomy compared with WT mice. Furthermore eNOS-KO-Nx also was increased excretion of albunuria after uni-nephrectomy. On the other hand, the ECeNOS-TG-Nx group exhibited enhanced compensatory renal hypertrophy than the other two groups. Treatment with BAY significantly enhanced compensatory renal hypertrophy in the eNOS-KO-Nx mice. Conclusions: Reduction of eNOS-NO bioavailability, as a endothelial dysfunction, may induce failure of compensatory hypertrophy and accelerate progressive renal dysfuction.