Meta-analytic evaluation of the effect of renal denervation in the treatment of essential hypertension in SHR rats

Essential hypertension (EH) is diagnosed in 90 % of people suffering from arterial hypertension (HTN). Along with drug therapy, renal denervation (RD) is used in clinical practice to reduce blood pressure (BP) in EH. In experimental studies, hypertension in SHR rats is a model of EH.
The aim of the work is to study, using a meta-analysis, the effect of RD on BP in SHR rats and its dependence on the stage of EH, initial BP, “white coat syndrome”, diet, presence of renal failure, and the method of the procedure.
Materials and methods. For the meta-analysis, 55 studies were selected that presented the level of BP in SHR rats after RD. In 51 studies, rats with two kidneys were subjected to RD (in 8 studies, unilateral total RD was studied, in 41 studies, bilateral RD (in 3 studies, afferent nerves were removed, in 5 studies, total denervation of the kidneys was performed using the radiofrequency method, in the rest, total denervation was performed using the surgical-chemical method). In 5 publications, RD effect was studied in rats with two kidneys kept on a high-salt diet. In 4 studies, RD was performed on rats with one kidney (the second kidney was removed).
Results. Bilateral total RD (both surgical-chemical and radiofrequency) effectively reduces BP in SHR rats with both standard and high-salt diets, and slows down, but does not prevent, the development of EH. After RD changes in systolic blood pressure are –23,59 [–27,88, –19,29] mmHg (–8.4 [–16.8, –6.4] %), changes in diastolic blood pressure are –19.96 [–23.74, –16.19] mmHg (–12.14 [–17.69, –6.15] %). In addition, bilateral total RD reduces the activity of the renin-angiotensin system and the level of norepinephrine. The observed antihypertensive effect of RD is approximately 2 times lower with telemetric recording of BP than with manual measurement on the tail artery, which indicates a decrease in the “white coat” syndrome after RD. With preservation of both kidneys, unilateral RD does not cause a decrease in BP.
Conclusion. Renal nerves make a significant contribution to the maintenance of EH, affecting the level of BP both at rest and under emotional stress. However, additional studies are required to resolve the issue of the role of afferentation from the kidneys in maintaining EH.

1. Ma J, Chen X. Advances in pathogenesis and treatment of essential hypertension. Front Cardiovasc Med. 2022;9:1003852. doi:10.3389/fcvm .2022.1003852

2. Davis MI, Filion KB, Zhang D, Eisenberg MJ, Afilalo J, Schiffrin EL, Joyal D. Effectiveness of renal denervation therapy for resistant hypertension: a systematic review and meta-analysis. J Am Coll Cardiol. 2013;62(3):231–241. doi:10.1016/j.jacc.2013.04.010

3. Fadl Elmula FE, Jin Y, Yang WY, Thijs L, Lu YC, Larstorp AC, et al; European Network Coordinating Research On Renal Denervation (ENCOReD) Consortium. Meta-analysis of randomized controlled trials of renal denervation in treatment-resistant hypertension. Blood Press. 2015;24(5):263–74. doi:10.3109/08037051.2015.1058595

4. Katsurada K, Ogoyama Y, Imai Y, Patel KP, Kario K. Renal denervation based on experimental rationale. Hypertens Res. 2021;44(11):1385–1394. doi:10.1038/s41440-021-00746-7

5. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to Meta-analysis. Wiley: Chichester, 2009. 421 p

6. Andrade TU, Franquini JV, Cabral AM, Vasquez EC, Araújo MT, Moysés MR et al. Acute obstructive apnea produces natriuresis in spontaneously hypertensive rats (SHR) by a renal nerve-dependent. Clin Exp Hypertens. 2010;32(8):555–9. doi:10. 3109/10641963.2010.503296

7. Beach RE, DuBose TD Jr. Adrenergic regulation of (Na+, K+)-ATPase activity in proximal tubules of spontaneously hypertensive rats. Kidney Int. 1990;38(3):402–8. doi:10.1038/ki.1990.219

8. Boer PA, Morelli JM, Figueiredo JF, Gontijo JA. Early altered renal sodium handling determined by lithium clearance in spontaneously hypertensive rats (SHR): role of renal nerves. Life Sci. 2005;76(16):1805–15. doi:10.1016/j.lfs.2004.09.029

9. Cai XN, Wang CY, Cai Y, Peng F. Effects of renal denervation on blood-pressure response to hemorrhagic shock in spontaneously hypertensive rats. Chin J Traumatol. 2018;21(5):293–300. doi:10.1016/j.cjtee.2018.09.001

10. Dias LD, Casali KR, Leguisamo NM, Azambuja F, Souza MS, Okamoto M, et al. Renal denervation in an animal model of diabetes and hypertension: impact on the autonomic nervous system and nephropathy. Cardiovasc Diabetol. 2011;10:33. doi:10.1186/1475-2840-10-33

11. DiBona GF, Sawin LL. Exaggerated natriuresis in experimental hypertension. Proc Soc Exp Biol Med. 1986;182(1):43–51. doi:10.3181/00379727-182-42306

12. Fink GD, Phelps JT. Can we predict the blood pressure response to renal denervation? Auton Neurosci. 2017; 204:112–118. doi:10.1016/j.autneu.2016.07.011

13. Gao J, Kerut EK, Smart F, Katsurada A, Seth D, Navar LG, Kapusta DR. Sympathoinhibitory effect of radiofrequency renal denervation in spontaneously hypertensive rats with established hypertension. Am J Hypertens. 2016;29(12):1394–1401. doi:10.1093/ajh/hpw089

14. Gattone VH 2nd, Shattuck M, Luft FC, Overhage JM, Willis LR, Evan AP. Effect of denervation on the afferent arteriole in the SHR. Jpn Heart J. 1984;25(5):745–53. doi:10.1536/ihj.25.745

15. Girchev RA, Bäcker A, Markova PP, Kramer HJ. Interaction of endothelin with renal nerves modulates kidney function in spontaneously hypertensive rats. Kidney Blood Press Res. 2006;29(2):126–34. doi:10.1159/000094571

16. Greenberg S, Osborn JL. Relationship between sodium balance and renal innervation during hypertension development in the spontaneously hypertensive rat. J Hypertens. 1994;12(12): 1359–64

17. Han W, Wang M, Zhai X, Gan Q, Guan S, Qu X. Chemical renal denervation-induced upregulation of the ACE2/Ang (1–7)/Mas axis attenuates blood pressure elevation in spontaneously hypertensive rats. Clin Exp Hypertens. 2020;42(7):661–668. doi:1 0.1080/10641963.2020.1772812.

18. Hayakawa K, Kimura M, Yamori Y. Role of the renal nerves in gamma-aminobutyric acid-induced antihypertensive effect in spontaneously hypertensive rats. Eur J Pharmacol. 2005;524(1–3):120–5. doi:10.1016/j.ejphar.2005.09.020

19. Hohl M, Lauder L, Sevimli Ö, Tokcan M, Wagmann L, Götzinger F et al. Efficacy of Antihypertensive Drugs of Different Classes After Renal Denervation in Spontaneously Hypertensive Rats. Hypertension. 2023;80(6):e90‑e100. doi:10.1161/HYPERTENSIONAHA.122.20756

20. Huang J, Huang H, Pan W, Ou D, Dai W, Lin Y et al. Renal denervation attenuates cardiac hypertrophy in spontaneously hypertensive rats via regulation of autophagy. Mol Med Rep. 2017;16(2):2023–2029. doi:10.3892/mmr.2017.6790

21. Ikeda S, Shinohara K, Kashihara S, Matsumoto S, Yoshida D, Nakashima R et al. Contribution of afferent renal nerve signals to acute and chronic blood pressure regulation in stroke-prone spontaneously hypertensive rats. Hypertens Res. 2023;46(1):268–279. doi:10.1038/s41440-022-01091-z

22. Iliescu R, Yanes LL, Bell W, Dwyer T, Baltatu OC, Reckelhoff JF. Role of the renal nerves in blood pressure in male and female SHR. Am J Physiol Regul Integr Comp Physiol. 2006;290(2): R341–4. doi:10.1152/ajpregu.00035.2005

23. Iversen BM, Kvam FI, Mørkrid L, Sekse I, Ofstad J. Effect of cyclooxygenase inhibition on renal blood flow autoregulation in SHR. Am J Physiol. 1992;263(3 Pt 2): F534–9. doi:10.1152/ajprenal.1992.263.3.F534

24. Jiang W, Tan L, Guo Y, Li X, Tang X, Yang K. Effect of renal denervation procedure on left ventricular hypertrophy of hypertensive rats and its mechanisms. Acta Cir Bras. 2012;27(11):815–20. doi:10.1590/s0102-86502012001100012

25. Katsuki M, Shinohara K, Kinugawa S, Hirooka Y. The effects of renal denervation on blood pressure, cardiac hypertrophy, and sympathetic activity during the established phase of hypertension in spontaneously hypertensive rats. Hypertens Res. 2024;47(4):1073–1077. doi:10.1038/s41440-024-01596-9

26. Kline RL, Kelton PM, Mercer PF. Effect of renal denervation on the development of hypertension in spontaneously hypertensive rats. Can J Physiol Pharmacol. 1978;56(5):818–22. doi:10.1139/y78-128

27. Kline RL, Stuart PJ, Mercer PF. Effect of renal denervation on arterial pressure and renal norepinephrine concentration in Wistar-Kyoto and spontaneously hypertensive rats. Can J Physiol Pharmacol. 1980;58(11):1384–8. doi:10.1139/y80-209

28. Koepke JP, DiBona GF. High sodium intake enhances renal nerve and antinatriuretic responses to stress in spontaneously hypertensive rats. Hypertension. 1985;7(3 Pt 1):357–63

29. Koepke JP, Jones S, DiBona GF. Sodium responsiveness of central alpha 2‑adrenergic receptors in spontaneously hypertensive rats. Hypertension. 1988;11(4):326–33. doi:10.1161/01.hyp.11.4.326

30. Krueger AD, Lee JY, Yang PC, Papaioannou SE, Walsh GM. Selective vasodilation produced by renal denervation in adult spontaneously hypertensive rats. Hypertension. 1986;8(5):372–8. doi:10.1161/01.hyp.8.5.372

31. Lappe RW, Todt JA, Wendt RL. Mechanism of action of vasoconstrictor responses to atriopeptin II in conscious SHR. Am J Physiol. 1985;249(6 Pt 2): R781–6. doi:10.1152/ajpregu.1985.249.6.R781

32. Lee JY, Walsh GM. Systemic and regional haemodynamic effects of renal denervation in spontaneously hypertensive rats. J Hypertens. 1983;1(4):381–6. doi:10.1097/00004872-198312000-00010

33. Li K, Tian J, Zhang Y, Xue Q, Lu C. Hypotensive effects of renal denervation in spontaneously hypertensive rat based on ultrasonic contrast imaging. Comput Med Imaging Graph. 2017;58:56–61. doi:10.1016/j.compmedimag.2017.01.006

34. Li KH, Lin JM, Luo SQ, Li MY, Yang YY, Li MM et al. Afferent renal denervation attenuates sympathetic overactivation from the paraventricular nucleus in spontaneously hypertensive rats. Am J Hypertens. 2024;37(7):477–484. doi:10.1093/ajh/hpae027

35. Liu D, Wang J, Hu H, Gu G, Ding R, Xie R, Cui W. The effects of renal nerve denervation on blood pressure and target organs in different hypertensive rat models. Int J Hypertens. 2021;2021:8615253. doi:10.1155/2021/8615253

36. Lundin S, Thorén P. Renal function and sympathetic activity during mental stress in normotensive and spontaneously hypertensive rats. Acta Physiol Scand. 1982;115(1):115–24. doi:10.1111/j.1748-1716.1982.tb07053.x

37. Machino T, Murakoshi N, Sato A, Xu D, Hoshi T, Kimura T, Aonuma K. Anti-hypertensive effect of radiofrequency renal denervation in spontaneously hypertensive rats. Life Sci. 2014;110(2):86–92. doi:10.1016/j.lfs.2014.06.015

38. Moreira NJD, Dos Santos F, Moreira ED, Farah D, de Souza LE, da Silva MB et al. Acute renal denervation normalizes aortic function and decreases blood pressure in spontaneously hypertensive rats. Sci Rep. 2020;10(1):21826. doi:10.1038/s41598-020-78674-8

39. Mozaffari MS, Jirakulsomchok S, Shao ZH, Wyss JM. High-NaCl diets increase natriuretic and diuretic responses in salt-resistant but not salt-sensitive SHR. Am J Physiol. 1991;260 (6 Pt 2): F890–7. doi:10.1152/ajprenal.1991.260.6.F890

40. Nakamura A, Johns EJ. Influence of the renal sympathetic nerves on renal renin and angiotensinogen gene expression in spontaneously hypertensive rats during development. J Hypertens. 1995;13(3):301–309

41. Norman RA Jr, Dzielak DJ. Role of renal nerves in onset and maintenance of spontaneous hypertension. Am J Physiol. 1982;243(2): H284–8. doi:10.1152/ajpheart.1982.243.2.H284

42. Pires NM, Igreja B, Moura E, Wright LC, Serrão MP, Soares-da-Silva P. Blood pressure decrease in spontaneously hypertensive rats following renal denervation or dopamine β-hydroxylase inhibition with etamicastat. Hypertens Res. 2015;38(9):605–12. doi:10.1038/hr.2015.50

43. Polhemus DJ, Gao J, Scarborough AL, Trivedi R, McDonough KH, Goodchild TT, et al. Radiofrequency renal denervation protects the ischemic heart via inhibition of GRK2 and increased nitric oxide signaling. Circ Res. 2016;119(3):470–80. doi:10.1161/CIRCRESAHA.115.308278

44. Raikwar N, Braverman C, Snyder PM, Fenton RA, Meyerholz DK, Abboud FM, Harwani SC. Renal denervation and CD161a immune ablation prevent cholinergic hypertension and renal sodium retention. Am J Physiol Heart Circ Physiol. 2019;317(3):H517–H530. doi:10.1152/ajpheart.00234.2019

45. Shweta A, Denton KM, Kett MM, Bertram JF, Lambert GW, Anderson WP. Paradoxical structural effects in the unilaterally denervated spontaneously hypertensive rat kidney. J Hypertens. 2005;23(4):851–9. doi:10.1097/01.hjh.0000163155.29740.d2

46. Skrzypecki J, Gawlak M, Huc T, Szulczyk P, Ufnal M. Renal denervation decreases blood pressure and renal tyrosine hydroxylase but does not augment the effect of hypotensive drugs. Clin Exp Hypertens. 2017;39(3):290–294. doi:10.1080/10641963.2016.1267191

47. Takabatake T, Ushiogi Y, Ohta K, Hattori N. Attenuation of enhanced tubuloglomerular feedback activity in SHR by renal denervation. Am J Physiol. 1990;258(4 Pt 2): F980–5. doi:10.1152/ajprenal.1990.258.4.F980

48. Tomoda F, Bergström G, Evans RG, Anderson WP. Evidence for decreased structurally determined preglomerular resistance in the young spontaneously hypertensive rat after 4 weeks of renal denervation. J Hypertens. 1997;15(10):1187–95. doi:10.1097/00004872-199715100-00018

49. Wang M, Han W, Zhang M, Fang W, Zhai X, Guan S, Qu X. Long-term renal sympathetic denervation ameliorates renal fibrosis and delays the onset of hypertension in spontaneously hypertensive rats. Am J Transl Res. 2018;10(12):4042–4053

50. Wei S, Li D, Zhang Y, Su L, Zhang Y, Wang Q et al. Perivascular radiofrequency renal denervation lowers blood pressure and ameliorates cardiorenal fibrosis in spontaneously hypertensive rats. PLoS One. 2017;12(4):e0176888. doi:10.1371/journal.pone.0176888

51. Winternitz SR, Katholi RE, Oparil S. Role of the renal sympathetic nerves in the development and maintenance of hypertension in the spontaneously hypertensive rat. J Clin Invest. 1980;66(5):971–8. doi:10.1172/JCI109966

52. Wu LL, Zhang Y, Li XZ, Du XL, Gao Y, Wang JX et al. Impact of selective renal afferent denervation on oxidative stress and vascular remodeling in spontaneously hypertensive rats. Antioxidants (Basel). 2022;11(5):1003. doi:10.3390/antiox11051003

53. Xiao B, Liu F, Jin YH, Jin YQ, Wang L, Lu JC, Yang XC. Renal sympathetic denervation attenuates left ventricle hypertrophy in spontaneously hypertensive rats by suppressing the Raf/MEK/ ERK signaling pathway. Clin Exp Hypertens. 2021;43(2):142–150. doi:10.1080/10641963.2020.1833022

54. Yoshida M, Yoshida E, Satoh S. Effect of renal nerve denervation on tissue catecholamine content in spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 1995;22(8):512–7. doi:10.1111/j.1440-1681.1995.tb02059.x

55. Nakagawa T, Hasegawa Y, Uekawa K, Ma M, Katayama T, Sueta D et al. Renal denervation prevents stroke and brain injury via attenuation of oxidative stress in hypertensive rats. J Am Heart Assoc. 2013;2(5): e000375. doi:10.1161/JAHA.113.000375

56. Sripairojthikoon W, Oparil S, Wyss JM. Renal nerve contribution to NaCl-exacerbated hypertension in spontaneously hypertensive rats. Hypertension. 1989;14(2):184–90. doi:10.1161/01.hyp.14.2.184

57. Maranon RO, Lima R, Mathbout M, do Carmo JM, Hall JE, Roman RJ, Reckelhoff JF. Postmenopausal hypertension: role of the sympathetic nervous system in an animal model. Am J Physiol Regul Integr Comp Physiol. 2014;306(4): R248–56. doi:10.1152/ajpregu.00490.2013

58. Maranon RO, Reckelhoff JF. Mechanisms responsible for postmenopausal hypertension in a rat model: roles of the renal sympathetic nervous system and the renin-angiotensin system. Physiol Rep. 2016;4(2):e12669. doi:10.14814/phy2.12669

59. McNally PG, Baker F, Mistry N, Walls J, Feehally J. Influence of nifedipine on cyclosporin A nephrotoxicity after unilateral nephrectomy in the spontaneously hypertensive rat. Clin Sci (Lond). 1991;81(2):271–9. doi:10.1042/cs0810271

60. Takeda K, Okajima H, Hayashi J, Kawasaki S, Sasaki S, Nakagawa M, Ijichi H. Attenuation of hypothalamo-sympathetic hyperactivity by renal denervation in experimental hypertensive rats. Clin Exp Hypertens A. 1987;9 Suppl 1:75–88. doi:10.3109/10641968709160165

61. Pioli MR, Ritter AM, de Faria AP, Modolo R. White coat syndrome and its variations: differences and clinical impact. Integr Blood Press Control. 2018;11:73–79. doi:10.2147/IBPC.S152761

62. Kopp UC, Cicha MZ, Smith LA. Impaired interaction between efferent and afferent renal nerve activity in SHR involves increased activation of alpha2‑adrenoceptors. Hypertension. 2011; 57(3):640–7. doi:10.1161/HYPERTENSIONAHA.110.166595

63. Pekarskiy SE, Baev AE, Mordovin VF, Ripp TM, Semke GV, Falkovskaya AV et al. Sympathetic renal denervation: elimination of “white coat” effect. Arterial’naya Gipertenziya (Arterial Hypertension). 2014;20(2):101–105. doi:10.18705/1607-419X-2014-20-2-101-105. In Russian.

64. Osborn JW, Tyshynsky R, Vulchanova L. Function of renal nerves in kidney physiology and pathophysiology. Annu Rev Physiol. 2021;83:429–450. doi:10.1146/annurev-physiol-031620-091656

65. Zheng H, Patel KP. Integration of renal sensory afferents at the level of the paraventricular nucleus dictating sympathetic outflow. Auton Neurosci. 2017;204:57–64. doi:10.1016/j.autneu.2016.08.008

66. Banek CT, Gauthier MM, Baumann DC, Van Helden D, Asirvatham-Jeyaraj N, Panoskaltsis-Mortari A et al. Targeted afferent renal denervation reduces arterial pressure but not renal inflammation in established DOCA-salt hypertension in the rat. Am J Physiol Regul Integr Comp Physiol. 2018;314(6):R883–R891. doi:10.1152/ajpregu.00416.2017

67. Banek CT, Knuepfer MM, Foss JD, Fiege JK, Asirvatham-Jeyaraj N, Van Helden D et al. Resting afferent renal nerve discharge and renal inflammation: elucidating the role of afferent and efferent renal nerves in deoxycorticosterone acetate salt hypertension. Hypertension. 2016;68(6):1415–1423. doi:10.1161/HYPERTENSIONAHA.116.07850