Chronic kidney disease (CKD) is affecting increased numbers of people across the world, and there remains no effective treatment strategy. Sympathetic nerve activation has been recognized as an important factor in the development and progression of cardiovascular disease, hypertension, and CKD. Catheter-guided renal denervation is useful to control blood pressure (BP) in patients with resistant hypertension and CKD. Sympathetic nerve-derived norepinephrine (NE) has been implicated in tissue homeostasis and the progression of various diseases, including CKD. The molecular mechanisms and signaling pathways triggered by sympathetic nerve activation, which drive renal inflammation and fibrogenesis in CKD progression, remain undefined. Presented here is the detailed methodology for renal denervation (RDNx) in experimental models of CKD. The results show that this method effectively ablates the renal nerve, as evidenced by the loss of tyrosine hydroxylase immunoreactivity and levels of kidney NE. This results in the suppression of renal tubular injury, inflammation, and fibrogenesis in CKD models. Competence of surgeons performing surgical procedures to denervate the kidney is a requirement to achieve consistent results. RDNx can be utilized to study the roles of renal nerve, nerve-derived neurotransmitters, and factors, as well as unveil their downstream signaling pathways. Defining the molecular mechanisms and underlying functions will lead to the design of novel therapeutic interventions for CKD, regardless of its etiology (e.g., diabetes, hypertension, and cardiovascular complications).