Comparison of the effects of renal denervation at early or advanced stages of hypertension on cardiac, renal, and adipose tissue pathology in Dahl salt-sensitive rats

Abstract

Renal denervation (RDN) has emerged as a novel therapy for drug-resistant hypertension. We here examined the effects of RDN at early versus advanced stages of hypertension on blood pressure and organ pathology in rats with salt-sensitive hypertension. Dahl salt-sensitive (DahlS) rats fed an 8% NaCl diet from 6 weeks of age were subjected to RDN (surgical ablation and application of 10% phenol in ethanol) or sham surgery at 7 (early stage) or 9 (advanced stage) weeks and were studied at 12 weeks. RDN at early or advanced stages resulted in a moderate lowering of blood pressure. Although RDN at neither stage affected left ventricular (LV) and cardiomyocyte hypertrophy, it ameliorated LV diastolic dysfunction, fibrosis, and inflammation at both stages. Intervention at both stages also attenuated renal injury as well as downregulated the expression of angiotensinogen and angiotensin-converting enzyme (ACE) genes and angiotensin II type 1 receptor protein in the kidney. Furthermore, RDN at both stages inhibited proinflammatory gene expression in adipose tissue. The early intervention reduced both visceral fat mass and adipocyte size in association with downregulation of angiotensinogen and ACE gene expression. In contrast, the late intervention increased fat mass without affecting adipocyte size as well as attenuated angiotensinogen and ACE gene expression. Our results thus indicate that RDN at early or late stages after salt loading moderately alleviated hypertension and substantially ameliorated cardiac and renal injury and adipose tissue inflammation in DahlS rats. They also suggest that cross talk among the kidney, cardiovascular system, and adipose tissue may contribute to salt-sensitive hypertension.

Beneficial effects of renal denervation on heart, kidneys, and adipose tissue beyond antihypertensive effect: is it independent of systemic sympathetic activity?

“…Therefore, it is often speculated that the organprotective effects of RDN may be associated with its sympathoinhibitory effect; however, this remains unclear because most clinical and animal studies have not evaluated sympathetic activity. Interestingly, the present study by Nagata et al demonstrated the cardiorenal protective effects of RDN without decreasing systemic sympathetic nerve activity [2]. We also demonstrated that RDN attenuated blood pressure elevation probably due to decreased activity of the circulating RAS by inhibition of efferent renal nerve activity, without decreasing sympathetic outflow in young stroke-prone spontaneously hypertensive rats [8].…”

“…The present study by Nagata et al reported the effects of RDN at early versus advanced stages of hypertension on blood pressure elevation and organ pathology, including kidney, heart, and adipose tissue, in Dahl salt-hypertensive rats fed 8% NaCl diet from 6 weeks of age [2]. The authors demonstrated that RDN at early stage (7 weeks of age) or advanced stage (9 weeks of age) attenuated blood pressure elevation.…”

“…Therefore, RDN, which denervates both efferent and afferent renal nerves, can decrease the activity of circulating RAS by reducing renin release through denervated efferent renal nerves and reduce central sympathetic outflow through denervated afferent renal nerves. This study by Nagata et al showed that RDN at advanced stage decreased the parameters of circulating RAS, including plasma renin activity and plasma angiotensin II concentration, whereas RDN at either stage did not change the urinary norepinephrine level, an index of systemic sympathetic activity in the Dahl saltsensitive rats [2]. In the heart and kidney, the local RAS operates in close interaction with the circulating RAS: the tissues may take up the circulating renin [5].…”