Objective and Methods: Hypertensive nephropathy is associated by increased renal sympathetic nerve activity. Alpha2A-adrenoceptors (alpha2A-AR) regulate sympathetic tone by controlling norepinephrine (NE) release by a negative feedback mechanism. Recently, we have shown that deletion of alpha2A-adrenoceptors increases renal sympathetic neurotransmission. To investigate whether deletion of alpha2A-AR play a role in the development of hypertensive nephropathy, we induced hypertension by infusing angiotensin (Ang)II (1000ng/kg/min) for 4 weeks in uninephrectomized wild-type (WT) and alpha2A-AR knockout (alpha2A-AR-/-) mice on an FVB background. Blood pressure was assessed by radiotelemetry. Results: NE release stimulated by renal nerve stimulation 5Hz was significantly higher in untreated kidneys of alpha2A-AR-/- compared controls. During AngII infusion (1000ng/kg/min) urinary NE excretion was significantly higher in alpha2A-AR-/- than control mice (4.3±0.6 vs. 2.1±0.4mg/dl creatinine, P <0.05). In line with an increased sympathetic NE release, the severity of hypertension caused by AngII infusion was significantly higher in alpha2A-AR-/- mice compared to control mice (176±4 vs. 163±3mmHg, P <0.01). Moreover, albuminuria (140±24 vs. 66±19mg/mg creatinine, P <0.05) as well as kidney injury assessed by glomerular injury score and renal fibrosis were accelerated and kidney function measured by cystatin C (1082±66 vs. 906±52ng/ml, P<0.05) was significantly decreased in alpha2A-AR-/- compared to WT mice. To test whether reduced renal sympathetic activity reversed this effect, renal nerve denervation (RDN) was performed in alph2A-AR-/- mice. RDN reduced renal NE content by 70%. In alpha2A-AR-/- mice, RDN reduced the severity of AngII induced hypertension 138±9 vs. 169± 11mmHg, P<0.05) and albuminuria compared to non-denervated alpha2A-AR-/- mice. Conclusion: Deletion of alpha2A-ARs exaggerates hypertensive nephropathy by increasing sympathetic NE activity. Reduction of NE release by RDN reduced blood pressure and albuminuria in alpha2A-AR-/- mice suggesting an important role of renal sympathetic tone in the pathogenesis of hypertensive nephropathy.