PP.11.16: RENAL DENERVATION REVERSES THE DEVELOPMENT OF JUVENILE HYPERTENSION, RENAL DYSFUNCTION AND GLOMEROSCLEROSIS SECONDARY TO NEONATAL HYPERLEPTINAEMIA. (June 2015)

• Record Type: Journal Article
• Authors: Samuelsson, A.; Fernandes, R.; Alderman, V.; Blasco, N. Maicas; Bramham, K.; Horsfield, C.; Joles, J.; Pombo, J.; Poston, L.
• Is Part Of: Journal of hypertension. Volume 33(2015)Supplement 1
• Publication Date: 2015-06
• Subjects: Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/01.hjh.0000468048.89248.f0
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : Objective: To determine the effects of bilateral renal denervation (DNX) and unilateral renal denervation (UNX) on renal function and structure in young male and female hypertensive rats, secondary to neonatal hyperleptinaemia. Design and method: Neonatal rats were treated with leptin (L-Tx; 3 mg/kg IP) or saline (S-Tx), postnatal day 9–14. Bilateral renal denervation (DNX) or sham-operation (SHAM) was performed at day 22. At 30 days of age, rats were allocated to one of two procedures designed to examine renal structure and function. A further group underwent unilateral renal denervation (UNX). In UNX and SHAM group, either the kidneys were perfusion-fixed for stereological estimates of glomerular dimensions and glomerulosclerosis, or the kidneys were frozen and used for qPCR and immunohistochemistry. Results: Bilateral renal denervation recovered the juvenile hypertension in L-Tx rats. Mean arterial pressure was approximately 20 mmHg lower in the L-Tx DNX versus L-Tx SHAM rats. Unilateral renal denervation showed no effect on blood pressure, but resulted in decreased oxidative stress (Nox-4, Nitrotyrosine) and injury (NGAL, Kim-1 and caspase-3) and improved glomerulosclerosis. Glomerular filtration rate (GFR) was rescued in L-TX-DNX (male, 1.4 ± 0.1, female, 0.9 ± 0.1 ml/min) compared with L-Tx-SHAM (male, 1.0 ± 0.1, female, 0.5 ± 0.1 ml/min; P < 0.05). L-Tx rats also showed altered sodium retention, ENAC (epithelial sodium channel) activity, and urinary renin and angiotensinogen concentrations which all became normalised after DNX surgery. Conclusions: This study provides incontrovertible evidence that renal nerve activation (RSNA) is the primary mechanism instigating juvenile hypertension and renal fibrogenesis, secondary to neonatal hyperleptinaemia. Our data implicates that increased RSNA mediate changes in intrarenal RAS and oxidative stress which initiate the renal dysfunction and structural malformations as tubular damage and fibrogenesis. Renal denervation may therefore be a putative therapeutic strategy for preventing, reversing or limiting primary hypertension and early kidney dysfunction. Furthermore, understanding the mechanisms by which renal denervation improves oxidative stress and renal injury will further the possibility to target new therapeutically strategies for the early prevention of hypertension.