Contribution of the Renal Nerves to Hypertension in a Rabbit Model of Chronic Kidney Disease

Abstract

Overactivity of the sympathetic nervous system and high blood pressure are implicated in the development and progression of chronic kidney disease (CKD) and independently predict cardiovascular events in end-stage renal disease. To assess the role of renal nerves, we determined whether renal denervation (RDN) altered the hypertension and sympathoexcitation associated with a rabbit model of CKD. The model involves glomerular layer lesioning and uninephrectomy, resulting in renal function reduced by one-third and diuresis. After 3-week CKD, blood pressure was 13±2 mm Hg higher than at baseline ( P <0.001), and compared with sham control rabbits, renal sympathetic nerve activity was 1.2±0.5 normalized units greater ( P =0.01). The depressor response to ganglion blockade was also +8.0±3 mm Hg greater, but total norepinephrine spillover was 8.7±3.7 ng/min lower (both P <0.05). RDN CKD rabbits only increased blood pressure by 8.0±1.5 mm Hg. Renal sympathetic activity, the response to ganglion blockade and diuresis were similar to sham denervated rabbits (non-CKD). CKD rabbits had intact renal sympathetic baroreflex gain and range, as well as normal sympathetic responses to airjet stress. However, hypoxia-induced sympathoexcitation was reduced by −9±0.4 normalized units. RDN did not alter the sympathetic response to hypoxia or airjet stress. CKD increased oxidative stress markers Nox5 and MCP-1 (monocyte chemoattractant protein-1) in the kidney, but RDN had no effect on these measures. Thus, RDN is an effective treatment for hypertension in this model of CKD without further impairing renal function or altering the normal sympathetic reflex responses to various environmental stimuli.

Renal denervation does not affect hypertension or the renin-angiotensin system in a rodent model of juvenile-onset polycystic kidney disease: clinical implications

“…In the literature, the impact of RDN on both systemic and intrarenal RAS has shown to be variable. Following RDN, a decrease in plasma renin activity has been shown in a rabbit model of hypertension secondary to chronic kidney disease 14 and a decrease in renal renin is seen in a mouse model of neurogenic hypertension 13 , while in the spontaneously hypertensive rat model of essential hypertension, total RDN had no effect plasma renin activity or kidney renin content 46 . In human clinical studies, RDN similarily had no impact on circulating renin in patients with resistant hypertension 47 .…”

“…In chronic kidney disease, data from preclinical 14 and clinical studies 15 has shown RDN can produce beneficial effects on blood pressure, cardiac and renal function. It is proposed that both sympathetic and sensory nerves are involved, as bilateral nephrectomy in chronic kidney disease patients reduces blood pressure and sympathetic activation, with the latter appearing to be mediated by an afferent signal arising in the diseased kidneys 16 .…”

Renal denervation: recent developments in clinical and preclinical research

“…Beyond hypertension, renal denervation [23] and afferent denervation [24] were found to be renoprotective in a rabbit chronic kidney disease model. In a rat model of polycystic kidney disease, elevated afferent renal nerve activity was observed at baseline and afferent or total denervation attenuated cystogenesis [25].…”

Pathomechanism of oxidative stress in cardiovascularrenal remodeling and therapeutic strategies

“…Variations in the perfusion pressure in the kidneys are detected by intrarenal baroreceptors, which modulate the renin-angiotensin-aldosterone system (RAAS). There is evidence that injured kidneys have aberrant sympathetic nerve activity which overrides the negative feedback loop on efferent renal sympathetic nerve activity thereby resulting in chronically increased systemic blood pressure [ 12 ]. In addition, hypertension causes tubulointerstitial fibrosis, which is associated with reduced secretory solute clearance, while reduced estimated glomerular filtration rate (eGFR) is linked to greater left ventricular wall thickness that predisposes patients to CVD [ 13 ].…”