Excessive activation of the sympathetic nervous system is one of the pathophysiological hallmarks of hypertension. Renal denervation (RDN), a neuromodulation therapy that modifies the circulatory regulatory system, has attracted attention for its potential to reduce the incidence and severity of cardiovascular diseases. The kidneys are the major regulators of circulating fluid volume, and their dysfunction is directly linked to the pathogenesis of hypertension. This treatment involves partial blockade of the renal sympathetic nervous system, which is an organ-connected pathway between the brain and the kidneys. Recently, published randomized controlled trials (i.e., the SPYRAL HTN-OFF MED/ON MED trial and the RADIANCE-HTN SOLO/TRIO trial) have shown that catheter-based RDN has a clear antihypertensive effect [1,2,3,4] and is expected to expand the therapeutic targets for chronic kidney disease and heart failure in addition to hypertension. However, before RDN can be introduced into the clinic, an accurate and efficient procedure must be established. Furthermore, the detailed mechanism of the antihypertensive effect of RDN has not been fully elucidated.
In a study published in this issue of Hypertension Research [5], Lai et al. examined the effect of selective RDN on the intrarenal renin-angiotensin system (RAS) and transporters involved in sodium and water reabsorption. The study was an extension of previous work from the same laboratory focusing on the method of RDN for the identification of optimal ablation targets [6]. Selective RDN, which involves ablation of sites associated with strong blood pressure (BP) elevations in response to renal nerve stimulation (RNS), showed a greater BP-lowering effect than RDN at weak BP-elevation response sites; it also resulted in a lower level of tyrosine hydroxylase and a lower content of norepinephrine in the kidneys.
A measurement of kidney norepinephrine content was performed for verification of experimental RDN. Surgical cutting of renal nerves performed in rodents has been shown to reduce the renal norepinephrine content to under 5–10% of that seen in innervated kidneys [7]. It is unknown how much catheter-based RDN reduces renal norepinephrine content in humans. The current study and previous reports demonstrate that catheter-based RDN reduces renal norepinephrine content to under 30–50% and under 25% of control levels as well as producing significant BP-lowering effects in canines and swine, respectively [5, 8]. It is important to note that selective RDN, which involves ablation at sites associated with strong BP-elevations in response to RNS, resulted in a lower renal norepinephrine level than ablation at weak BP-elevation response sites in canines in the current study.
The current study was the first to demonstrate that selective RDN significantly attenuated release of renin; synthesis of angiotensinogen; and the expression of angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and angiotensin II type 1 receptor (AT1R) in canines as a large animal model. These effects were accompanied by enhanced expression of ACE2, Ang (1–7), and Mas-receptor (Mas-R). Previously, Lu et al. reported that plasma levels of renin and Ang II are decreased 3 months after RDN in canines [9]. Sharp III et al. reported that serum and renal Ang I and Ang II levels are decreased 3 months after RDN in swine [8]. Mahfoud et al. reported that plasma renin activity levels for RDN patients are significantly lower at 3 months after RDN than at baseline [10]. The findings in the current study, together with these findings in previous reports, suggest that RDN inhibits the intrarenal RAS as well as the systemic RAS, possibly acting in a renoprotective manner. Additionally, the current study shows that selective RDN significantly reduces the expression of renal aquaporin (AQP)1 and AQP2 and decreases the phosphorylation of sodium-potassium-chloride cotransporter 2 (NKCC2) levels and the trafficking of NKCC2 to the apical membrane, alleviating water and sodium reabsorption. These RDN-mediated modulations of the major transporters associated with water and sodium reabsorption appear to be favorable therapeutic effects for heart failure (Fig. 1).
Renal nerves contain sympathetic efferent fibers and sensory afferent fibers. It is plausible that the antihypertensive effect of RDN is mediated mainly by sympathetic efferent denervation-induced suppression of renin secretion, sodium reabsorption, and renal vascular resistance [11, 12]. Additionally, it has been proposed that specific afferent denervation modulates sensory signals from the kidneys to the central nervous system to suppress sympathetic outflow [11, 12]. However, the role of afferent renal nerves in the regulation of the cardiovascular system has not been fully elucidated. There are different types of afferent fibers that have sympathoexcitatory effects and sympathoinhibitory effects in response to RNS. The optimal RDN target for treating hypertension, which is a site that responds to RNS with strong BP elevation, seems to include abundant sympathoexcitatory afferent fibers. However, it is unclear whether RDN-mediated intrarenal neurohormonal changes are induced by afferent denervation or efferent denervation. It has been reported that selective afferent renal denervation via capsaicin application suppresses the intrarenal RAS in a 2-kidney 1-clip model of renovascular hypertensive rats [13] and a 5/6 nephrectomy model of chronic kidney disease rats [14]. Interactions between some transporters associated with sodium reabsorption and the RAS or sympathetic nervous system have been reported. AT1 receptor blockade with candesartan prevents the upregulation of AQP2 expression, indicating that Ang II-mediated AT1R activation plays an important role in AQP2 expression [15]. Ang II-stimulated NKCC2 activation is related to phosphorylation and trafficking to the apical membrane [16]. On the other hand, norepinephrine reportedly increases renal expression of sodium-hydrogen exchanger 3 (NHE-3), sodium-bicarbonate cotransporter 1 (NBC-1), bumetanide-sensitive sodium-potassium-chloride cotransporter (BSC-1/NKCC2) and AQP2 in rats [17]. Recent studies have suggested that the expression of renal ENaC and AQP2 is enhanced in rats with heart failure but that this elevation is mitigated by RDN [18]. Another study has shown that the expression and functional activity of renal sodium-glucose cotransporter 2 (SGLT2) are enhanced in heart failure rats and reduced by RDN. That study also demonstrates that norepinephrine promotes the translocation of SGLT2 to the cell membrane in vitro [19]. These findings suggest that both afferent and efferent renal nerves contribute to the regulation of components of the intrarenal RAS and transporters involved in sodium and water reabsorption (Fig. 1).
In conclusion, the current paper by Lai et al. [5] confirms that selective RDN by RNS effectively exerts an antihypertensive effect in a hypertensive canine model and newly demonstrates possible underlying mechanisms in which selective RDN downregulates the expression of renal ACE, Ang II, and AT1R and upregulates the expression of renal ACE2, Ang (1–7) and Mas-R while restoring the expression of renal AQP1, AQP2, and NKCC2. These intrarenal neurohormonal modulations are potentially favorable for treating patients with chronic kidney disease and heart failure in addition to hypertension.
References
Bohm M, Kario K, Kandzari DE, Mahfoud F, Weber MA, Schmieder RE, et al. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN- OFF MED Pivotal): a multicentre, randomised, sham-controlled trial. Lancet 2020;395:1444–51.
Kandzari DE, Bohm M, Mahfoud F, Townsend RR, Weber MA, Pocock S, et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet 2018;391:2346–55.
Azizi M, Schmieder RE, Mahfoud F, Weber MA, Daemen J, Davies J, et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet. 2018;391:2335–45.
Azizi M, Sanghvi K, Saxena M, Gosse P, Reilly JP, Levy T, et al. Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial. Lancet. 2021;397:2476–86.
Lai Y, Zhou H, Chen W, Liu H, Liu G, Xu Y, et al. Intrarenal blood pressure modulation system differentially altered after renal denervation guided by different intensities of blood pressure responses. Hypertens Res. 2022. https://doi.org/10.1038/s41440-022-01047-3.
Liu H, Chen W, Lai Y, Du H, Wang Z, Xu Y, et al. Selective renal denervation guided by renal nerve stimulation in canine. Hypertension 2019;74:536–45.
Eriguchi M, Tsuruya K, Haruyama N, Yamada S, Tanaka S, Suehiro T, et al. Renal denervation has blood pressure-independent protective effects on kidney and heart in a rat model of chronic kidney disease. Kidney Int. 2015;87:116–27.
Sharp TE III, Polhemus DJ, Li Z, Spaletra P, Jenkins JS, Reilly JP, et al. Renal denervation prevents heart failure progression via inhibition of renin-angiotensin system. Am Coll Cardiol. 2018;72:2609–21.
Lu J, Ling Z, Chen W, Du H, Xu Y, Fan J, et al. Effects of renal sympathetic denervation using saline-irrigated radiofrequency ablation catheter on the activity of the renin-angiotensin system and endothelin-1. J Renin Angiotensin Aldosterone Syst. 2014;15:532–9.
Mahfoud F, Townsend RR, Kandzari DE, Kario K, Schmieder RE, Tsioufis K, et al. Changes in plasma renin activity after renal artery sympathetic denervation. J Am Coll Cardiol. 2021;77:2909–19.
Kario K. Essential manual of 24 h blood pressure management: from morning to nocturnal hypertension. Chichester, West Sussex, UK; Malden, MA: John Wiley & Sons Inc.; 2015.
Osborn JW, Foss JD. Renal nerves and long-term control of arterial pressure. Compr Physiol. 2017;7:263–320.
Lopes NR, Milanez MIO, Martins BS, Veiga AC, Ferreira GR, Gomes GN, et al. Afferent innervation of the ischemic kidney contributes to renal dysfunction in renovascular hypertensive rats. Pflug Arch. 2020;472:325–34.
Veiga AC, Milanez MIO, Ferreira GR, Lopes NR, Santos CP, De Angelis K, et al. Selective afferent renal denervation mitigates renal and splanchnic sympathetic nerve overactivity and renal function in chronic kidney disease-induced hypertension. J Hypertens. 2020;38:765–73.
Kwon TH, Nielsen J, Knepper MA, Frøkiaer J, Nielsen S. Angiotensin II AT1 receptor blockade decreases vasopressin-induced water reabsorption and AQP2 levels in NaCl-restricted rats. Am J Physiol Ren Physiol. 2005;288:F673–84.
Gonzalez-Villalobos RA, Janjoulia T, Fletcher NK, Giani JF, Hguyen MTX, Riquier-Brison AD, et al. The absence of intrarenal ACE protects against hypertension. J Clin Invest. 2013;123:2011–23.
Sonalker PA, Tofovic SP, Bastacky SI, Jackson EK. Chronic noradrenaline increases renal expression of NHE-3, NBC-1, BSC-1, and aquaporin-2. Clin Exp Pharm Physiol. 2008;35:594–600.
Zheng H, Liu X, Katsurada K, Patel KP. Renal denervation improves sodium excretion in rats with chronic heart failure: effects on expression of renal ENaC and AQP2. Am J Physiol Heart Circ Physiol. 2019;317:H958–68.
Katsurada K, Nandi SS, Sharma NM, Patel KP. Enhanced expression and function of renal SGLT2 (sodium-glucose cotransporter 2) in heart failure: role of renal nerves. Circ Heart Fail. 2021;14:e008365.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Katsurada, K., Kario, K. Intrarenal neurohormonal modulation by renal denervation: benefits for chronic kidney disease and heart failure. Hypertens Res 46, 518–520 (2023). https://doi.org/10.1038/s41440-022-01104-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41440-022-01104-x