Renal Sympathetic Denervation Suppresses De Novo Podocyte Injury and Albuminuria in Rats With Aortic Regurgitation

Abstract

Background The presence of chronic kidney disease is a significant independent risk factor for poor prognosis in patients with chronic heart failure (CHF). However, the mechanisms and mediators underlying this interaction are poorly understood. In this study, we tested our hypothesis that chronic cardiac volume overload leads to de novo renal dysfunction by co-activating the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) in the kidney. We also examined the therapeutic potential of renal denervation and RAS inhibition to suppress renal injury in CHF. Methods and Results Sprague-Dawley rats underwent aortic regurgitation (AR) and were treated for 6 months with either vehicle, olmesartan [an angiotensin II (AngII) receptor blocker], or hydralazine. At 6 months, albuminuria and glomerular podocyte injury were significantly increased in AR rats. These changes were associated with increased urinary angiotensinogen excretion, kidney AngII and norepinephrine (NE) levels, as well as enhanced angiotensinogen and angiotensin type 1a receptor gene expression, and oxidative stress in renal cortical tissues. AR rats with renal denervation had decreased albuminuria and glomerular podocyte injury, which were associated with reduced kidney NE, angiotensinogen, AngII and oxidative stress. Renal denervation combined with olmesartan prevented podocyte injury and albuminuria induced by AR. Conclusions In this chronic cardiac volume overload animal model, activation of the SNS augments kidney RAS and oxidative stress, which act as crucial cardio-renal mediators. Renal denervation and olmesartan prevent the onset and progression of renal injury, providing new insight into the treatment of cardio-renal syndrome.

Cardiac Autonomic Neuropathy and Early Progressive Renal Decline in Patients with Nonmacroalbuminuric Type 1 Diabetes

“…The SNS is associated with other novel biomarkers of renal injury and GFR loss, including neurohormonal activation, markers of cell apoptosis, inflammation, and immune responses (45). For instance, among rats with induced aortic regurgitation, increased intrarenal production of angiotensin II, reactive oxygen species, and nicotinamide adenine dinucleotide phosphate oxidase components resulted in podocyte injury and subsequent albuminuriaeffects that are attenuated with renal SNS denervation (46). Similarly, the SNS activates proinflammatory pathways, including cytokines/chemokines (47).…”

Investigation of the mechanism underlying the antihypertensive effect of catheter-based radiofrequency renal sympathetic denervation in hypertensive dogs

“…If oxidative stress can be effectively inhibited during the pathogenesis of hypertension, hypertension may be effectively prevented and treated. Rafiq et al (12) found that radiofrequency RSD in rats with aortic regurgitation led to a reduction in renal norepinephrine, angiotensinogen and AngII, as well as an improvement in oxidative stress. The present study showed that in the high-fat diet-induced hypertension model, the AngII level decreased following radiofrequency RSD.…”

Cardiorenal Syndrome

“…Examples of this would include progressive CKD resulting from congenital or acquired chronic congestive heart failure or from repeated episodes of acute CRS. Animal studies and human observational evidence demonstrate that chronic heart failure leads to varying degrees of albuminuria/ proteinuria, progressive decline in GFR, and expression of renal injury biomarkers (32,33). Key to the pathophysiology is chronic activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system as a result of arterial underfilling and/or venous congestion.…”