Functional and molecular actions of renal nerve in experimental chronic renal failure

Abstract

The prevalence of chronic kidney disease (CKD) is increasing worldwide and the main contributors to CKD progression are arterial hypertension (AH) and diabetes. Despite advances in pharmacological treatments with antihypertensive and anti-diabetic drugs, the alarming number of patients with nephropathy shows the need for new therapeutic strategies. The sympathetic nervous system (SNS) has been highlighted as an important therapeutic target for AH through renal denervation in patients and experimental models. Clinical and experimental studies have shown that the denervation procedure, which removes both the renal sympathetic and sensory fibers, promotes not only renoprotective effects, but also improves cardiac and vascular function, glucose metabolism and insulin sensitivity. In CKD, several mechanisms lead to cardiac and renal dysfunction, such as the renin-angiotensin system (RAS), aldosterone, endothelin, inflammation, oxidative stress and fibrosis. The hypothesis of the present project is that the renal nerves play an important role in determining the cardiovascular and renal alterations in CKD. CKD will be induced by the experimental 5/6 nephrectomy model in Wistar rats. Total renal denervation, selective denervation of the renal afferent fibers and/or renin-angiotensin system blockade will be performed after 5 weeks of CKD induction, and 3 weeks later the following parameters will be evaluated: blood pressure, heart rate, sympathetic nerve activity to different beds, cardiac and renal function and fibrosis, systemic and renal oxidative stress and inflammation. In addition, tubular or glomerular proteinuria, NADPH oxidase subunits and Rho kinase activity marker, pMYPT1, will be evaluated by western blotting and serum copeptin and urinary angiotensinogen will be quantified by ELISA. Data obtained from the present project will contribute to the understanding of underlying mechanisms in AH and thereby contribute to the development and improvement of new therapeutic strategies to treat CKD. These studies will contribute to the understanding of mechanisms associated with the antihypertensive effect of renal denervation in humans and animal models. (AU)