OBJECTIVE: To determine the influence of the renal sympathetic nerves on the pathogenesis of septic acute kidney injury. DESIGN: Interventional control study to determine the effects of renal denervation in ovine hyperdynamic sepsis. SETTING: Research Institute. SUBJECTS: Twenty-four adult Merino ewes. INTERVENTIONS: The effects of infusion of angiotensin II and norepinephrine and induction of hyperdynamic sepsis by administration of live Escherichia coli were examined in control sheep and in sheep at 2 weeks after bilateral renal denervation (n = 10/group). MEASUREMENTS AND MAIN RESULTS: Systemic hemodynamics and renal function were measured in conscious sheep instrumented with flow probes on the pulmonary and renal arteries. Angiotensin II, but not norepinephrine, had a greater pressor effect in denervated animals. Sepsis increased cardiac output by 60 , renal blood flow by 35 , and arterial lactate by approximately four-fold. The denervated compared with the control group had a greater degree of hypotension during sepsis (68 vs 81 mm Hg; p = 0.003) and a reduction in the early polyuric response (from 496 to 160 mL at 2-8 hr of sepsis; p <0.001). Creatinine clearance decreased similarly in both groups. CONCLUSIONS: In experimental hyperdynamic sepsis, renal denervation was associated with greater hypotension and a loss of the initial diuresis, but no significant change in creatinine clearance. In sepsis, the renal nerves help support arterial pressure and determine the initial diuretic response, but septic acute kidney injury developed similarly in the innervated and denervated groups.