Over-activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of hypertension. In rodent models, juvenile offspring of obese dams exhibit sympathetic mediated hypertension and hyperphagia, increased adiposity and insulin resistance in adulthood which is associated with an exaggerated leptin surge in early postnatal life(1). We aimed to elucidate the mechanisms underlying RAAS and oxidative stress and the beneficial effects of renal denervation (RD) in a neonatal hyperleptinaemic rat model.Male and female Wistar rats were given intraperitoneal injections of leptin twice daily (L-Tx, 3mg/kg) from postnatal day 9 to 14, to mimic the exaggerated leptin surge in neonatal offspring of obese dams, versus saline treated (S-Tx). At 22 days of age, rats were subject to telemetry surgery performed under 3% isoflurane (inhaled) and probes were inserted into the arch of the aorta via the left carotid artery. After 7 days of baseline recordings each group was further divided into a RD group and a sham operated (SH) group to examine the effects of RD on blood pressure. RD was performed under isoflurane through an incision in the dorsal midline and all visible nerves were cut and painted with 10% phenol. RD was confirmed if noradrenaline content of renal tissue was <10% of the mean value in SH. The right kidneys were excised from sacrificed rats and stored at -80°C for gene expression analysis with all qPCR results normalised against the geometric mean of the housekeeper genes HPRT and TATABOX according to the geNorm method. Statistical analysis was performed using two-way ANOVA tests to compare neonatal treatment with surgery; significant results were those with a P value of <0.05. At 30 days of age, neonatal leptin rats demonstrated increased blood pressure, enhanced RAAS and decreased creatinine clearance [GFR, ml/min/kg, L-Tx, 2.8±0.1 vs. S-Tx, 3.5±0.2, n=6, p<0.05]. RD reduced 24-h mean arterial pressure (MAP) in male (L-Tx-SH, 114±2 mmHg vs. L-Tx-RD, 99±1 mmHg, P<0.0001, n=4-5) and female (L-Tx-SH, 115±3 mmHg vs. L-Tx-RD, 96±3 mmHg, P<0.0001, n=4-5) rats and improved renal function. Furthermore, RD normalised cortex expression of type-1a angiotensin II receptor (AT1a ) in L-Tx rats which was increased 100-fold in females and 4-fold in males compared to S-Tx. Aquaporin-2 (AQP2) has also been associated with angiotensin II induced hypertension and reactive oxygen species(2) and we observed reduced AQP2 expression concomitant with increased NADPH oxidase 4 (NOX4) expression.Thus RD significantly reduces angiotensin II induced hypertension, improves renal function and normalises the RAAS. These findings lend evidence to support the exciting prospect of RD as a future target for the treatment of hypertension in select population groups.