The onset of hypertension in metabolic syndrome is independent of renal sympathetic innervation.

Increased sympathetic tone and hypertension are hallmarks of metabolic syndrome and contribute to chronic kidney disease. Although renal sympathetic denervation transiently lowers blood pressure, its role in the development of metabolic and renal alterations remains unclear. Here, we evaluated the contribution of renal sympathetic input to the onset and progression of high-fat diet-induced alterations. Male Wistar rats underwent bilateral renal denervation before metabolic challenge and were fed a standard or high-fat diet for 8 or 12 wk. High-fat feeding induced hypertension, proteinuria, increased angiotensin II, and reduced creatinine clearance, urinary flow, and potassium excretion, independently of denervation. Renal norepinephrine content confirmed effective denervation and was not affected by diet. Denervation attenuated ketonuria in high-fat diet-fed rats. The phosphorylation of AKT, PI3K, and ERK1/2 in the kidney was modulated by interactions among diet, renal sympathetic input, and time. These findings indicate that renal sympathetic nerves contribute to early stages of metabolic dysregulation, whereas prolonged hypercaloric exposure overrides autonomic control and promotes cardiovascular and renal complications.