Afferent innervation of the ischemic kidney contributes to renal dysfunction in renovascular hypertensive rats

  • Nathalia R. Lopes
  • Maycon I. O. Milanez
  • Beatriz S. Martins
  • Amanda C. Veiga
  • Giovanna R. Ferreira
  • Guiomar N. Gomes
  • Adriana C. Girardi
  • Polliane M. Carvalho
  • Fernando N. Nogueira
  • Ruy R. Campos
  • Cássia T. Bergamaschi
  • Erika E. NishiEmail author
Integrative physiology
Part of the following topical collections:
  1. Integrative Physiology
  2. Integrative Physiology


The ablation of renal nerves, by destroying both the sympathetic and afferent fibers, has been shown to be effective in lowering blood pressure in resistant hypertensive patients. However, experimental studies have reported that the removal of sympathetic fibers may lead to side effects, such as the impairment of compensatory cardiorenal responses during a hemodynamic challenge. In the present study, we evaluated the effects of the selective removal of renal afferent fibers on arterial hypertension, renal sympathetic nerve activity, and renal changes in a model of renovascular hypertension. After 4 weeks of clipping the left renal artery, afferent renal denervation (ARD) was performed by exposing the left renal nerve to a 33 mM capsaicin solution for 15 min. After 2 weeks of ARD, we found reduced MAP (~ 18%) and sympathoexcitation to both the ischemic and contralateral kidneys in the hypertensive group. Moreover, a reduction in reactive oxygen species was observed in the ischemic (76%) and contralateral (27%) kidneys in the 2K1C group. In addition, ARD normalized renal function markers and proteinuria and podocin in the contralateral kidney. Taken altogether, we show that the selective removal of afferent fibers is an effective method to reduce MAP and improve renal changes without compromising the function of renal sympathetic fibers in the 2K1C model. Renal afferent nerves may be a new target in neurogenic hypertension and renal dysfunction.


Sympathetic nervous system Renovascular hypertension Afferent renal denervation Proteinuria 


Author contributions

Nathalia R. Lopes, Guiomar N. Gomes, Adriana C. Girardi, Fernando N. Nogueira, Ruy R. Campos, Cássia T. Bergamaschi, and Erika E. Nishi contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Nathalia R. Lopes, Maycon I. O. Milanez, Beatriz S. Martins, Amanda C. Veiga, Giovanna R. Ferreira, and Polliane M. Carvalho. The first draft of the manuscript was written by Nathalia R. Lopes and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding information

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001, by the São Paulo Research Foundation (FAPESP 18/02671-3 and 16/22140-7) and by the Brazilian National Research Council (CNPq 406233/2018-7, 0817/2018). NRL was a recipient of FAPESP scholarships (15/23858-6, 17/12383-2). RRC, ACCG, and CTB are recipients of the CNPq productive research fellowship.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.


  1. 1.
    Oparil S, Acelajado MC, Bakris GL, Berlowitz DR, Cífková R, Dominiczak AF, Grassi G, Jordan J, Poulter NR, Rodgers A, Whelton PK (2018) Hypertension. Nat Rev Dis Primers 4:18014–18021. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Campos RR, Oliveira-Sales EB, Nishi EE, Boim MA, Dolnikoff MS, Bergamaschi CT (2011) The role of oxidative stress in renovascular hypertension. Clin Exp Pharmacol Physiol 38:144–152. CrossRefPubMedGoogle Scholar
  3. 3.
    de Champlain J, Wu R, Girouard H, Karas M, EL Midaoui A, Laplante MA, Wu L (2004) Oxidative stress in hypertension. Clin Exp Hypertens 26:593–601CrossRefGoogle Scholar
  4. 4.
    Krum H, Schlaich MP, Sobotka PA, Böhm M, Mahfoud F, Rocha-Singh K, Katholi R, Esler MD (2014) Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 383:622–629. CrossRefPubMedGoogle Scholar
  5. 5.
    Papademetriou V, Tsioufis C, Doumas M (2014) Renal denervation and Symplicity HTN-3: “Dubium sapientiae initium” (doubt is the beginning of wisdom). Circ Res 115:211–214. CrossRefPubMedGoogle Scholar
  6. 6.
    Esler M, Guo L (2017) The future of renal denervation. Auton Neurosci 204:131–138. CrossRefPubMedGoogle Scholar
  7. 7.
    DiBona GF, Kopp UC (1997) Neural control of renal function. Physiol Rev 77:75–197CrossRefGoogle Scholar
  8. 8.
    Johansson M, Elam M, Rundqvist B, Eisenhofer G, Herlitz H, Lambert G, Friberg P (1999) Increased sympathetic nerve activity in renovascular hypertension. Circulation 99:2537–2542. CrossRefPubMedGoogle Scholar
  9. 9.
    Oliveira-Sales EB, Nishi EE, Carillo BA, Boim MA, Dolnikoff MS, Bergamaschi CT, Campos RR (2009) Oxidative stress in the sympathetic premotor neurons contributes to sympathetic activation in renovascular hypertension. Am J Hypertens 22:484–492. CrossRefPubMedGoogle Scholar
  10. 10.
    Schlaich MP, Esler MD, Fink GD, Osborn JW, Euler DE (2014) Targeting the sympathetic nervous system: critical issues in patient selection, efficacy, and safety of renal denervation. Hypertension 63:426–432. CrossRefPubMedGoogle Scholar
  11. 11.
    Ong J, Kinsman BJ, Sved AF, Rush BM, Tan RJ, Carattino MD, Stocker SD (2019) Renal sensory nerves increase sympathetic nerve activity and blood pressure in 2-kidney 1-clip hypertensive mice. J Neurophysiol 122:358–367. CrossRefPubMedGoogle Scholar
  12. 12.
    Nishi EE, Oliveira-Sales EB, Bergamaschi CT, Oliveira TG, Boim MA, Campos RR (2010) Chronic antioxidant treatment improves arterial renovascular hypertension and oxidative stress markers in the kidney in Wistar rats. Am J Hypertens 23:473–480. CrossRefPubMedGoogle Scholar
  13. 13.
    Veelken R, Vogel EM, Hilgers K, Amann K, Hartner A, Sass G, Neuhuber W, Tiegs G (2008) Autonomic renal denervation ameliorates experimental glomerulonephritis. J Am Soc Nephrol 19:1371–1378. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kiuchi MG, Maia GL, de Queiroz Carreira MA, Kiuchi T, Chen S, Andrea BR, Graciano ML, Lugon JR (2013) Effects of renal denervation with a standard irrigated cardiac ablation catheter on blood pressure and renal function in patients with chronic kidney disease and resistant hypertension. Eur Heart J 34:2114–2121. CrossRefPubMedGoogle Scholar
  15. 15.
    Weir MR (2007) Microalbuminuria and cardiovascular disease. Clin J Am Soc Nephrol 2:581–590. CrossRefPubMedGoogle Scholar
  16. 16.
    Mulder J, Hökfelt T, Knuepfer MM, Kopp UC (2013) Renal sensory and sympathetic nerves reinnervate the kidney in a similar time-dependent fashion after renal denervation in rats. Am J Phys Regul Integr Comp Phys 304:R675–R682. CrossRefGoogle Scholar
  17. 17.
    Foss JD, Wainford RD, Engeland WC, Fink GD, Osborn JW (2015) A novel method of selective ablation of afferent renal nerves by periaxonal application of capsaicin. Am J Phys Regul Integr Comp Phys 308:R112–R122. CrossRefGoogle Scholar
  18. 18.
    Shimokawa A, Kunitake T, Takasaki M, Kannan H (1998) Differential effects of anesthetics on sympathetic nerve activity and arterial baroreceptor reflex in chronically instrumented rats. J Auton Nerv Syst 72:46–54CrossRefGoogle Scholar
  19. 19.
    Iwashita S, Tanida M, Terui N, Ootsuka Y, Shu M, Kang D, Suzuki M (2002) Direct measurement of renal sympathetic nervous activity in high-fat diet-related hypertensive rats. Life Sci 71:537–546. CrossRefPubMedGoogle Scholar
  20. 20.
    Morgan DA, Anderson EA, Mark AL (1995) Renal sympathetic nerve activity is increased in obese Zucker rats. Hypertension 25:834–838. CrossRefPubMedGoogle Scholar
  21. 21.
    Morgan DA, Despas F, Rahmouni K (2015) Effects of leptin on sympathetic nerve activity in conscious mice. Phys Rep 3. CrossRefGoogle Scholar
  22. 22.
    Ramchandra R, Hood SG, Denton DA, Woods RL, McKinley MJ, McAllen RM, May CN (2009) Basis for the preferential activation of cardiac sympathetic nerve activity in heart failure. Proc Natl Acad Sci U S A 106:924–928. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wei SG, Felder RB (2002) Forebrain renin-angiotensin system has a tonic excitatory influence on renal sympathetic nerve activity. Am J Physiol Heart Circ Physiol 282:H890–H895. CrossRefPubMedGoogle Scholar
  24. 24.
    Malpas SC, Ninomiya I (1992) A new approach to analysis of synchronized sympathetic nerve activity. Am J Phys 263:H1311–H1317Google Scholar
  25. 25.
    Malpas SC, Ninomiya I (1992) The amplitude and periodicity of synchronized renal sympathetic nerve discharges in anesthetized cats: differential effect of baroreceptor activity. J Auton Nerv Syst 40:189–198CrossRefGoogle Scholar
  26. 26.
    Nishi EE, Lopes NR, Gomes GN, Perry JC, Sato AYS, Naffah-Mazzacoratti MG, Bergamaschi CT, Campos RR (2019) Renal denervation reduces sympathetic overactivation, brain oxidative stress, and renal injury in rats with renovascular hypertension independent of its effects on reducing blood pressure. Hypertens Res 42:628–640. CrossRefPubMedGoogle Scholar
  27. 27.
    Katholi RE, Whitlow PL, Winternitz SR, Oparil S (1982) Importance of the renal nerves in established two-kidney, one clip Goldblatt hypertension. Hypertension 4:166–174PubMedGoogle Scholar
  28. 28.
    Singh RR, Sajeesh V, Booth LC, McArdle Z, May CN, Head GA, Moritz KM, Schlaich MP, Denton KM (2017) Catheter-based renal denervation exacerbates blood pressure fall during hemorrhage. J Am Coll Cardiol 69:951–964. CrossRefPubMedGoogle Scholar
  29. 29.
    Converse RL, Jacobsen TN, Toto RD, Jost CM, Cosentino F, Fouad-Tarazi F, Victor RG (1992) Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 327:1912–1918. CrossRefPubMedGoogle Scholar
  30. 30.
    Zheng H, Katsurada K, Liu X, Knuepfer MM, Patel KP (2018) Specific afferent renal denervation prevents reduction in neuronal nitric oxide synthase within the paraventricular nucleus in rats with chronic heart failure. Hypertension 72:667–675. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Banek CT, Gauthier MM, Van Helden DA, Fink GD, Osborn JW (2019) Renal inflammation in DOCA-salt hypertension. Hypertension 73:1079–1086. CrossRefPubMedGoogle Scholar
  32. 32.
    Kim J, Padanilam BJ (2013) Renal nerves drive interstitial fibrogenesis in obstructive nephropathy. J Am Soc Nephrol 24:229–242. CrossRefPubMedGoogle Scholar
  33. 33.
    Silva-Aguiar RP, Bezerra NCF, Lucena MC, Sirtoli GM, Sudo RT, Zapata-Sudo G, Takiya CM, Pinheiro AAS, Dias WB, Caruso-Neves C (2018) O-GlcNAcylation reduces proximal tubule protein reabsorption and promotes proteinuria in spontaneously hypertensive rats. J Biol Chem 293:12749–12758. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  • Nathalia R. Lopes
    • 1
  • Maycon I. O. Milanez
    • 1
  • Beatriz S. Martins
    • 1
  • Amanda C. Veiga
    • 1
  • Giovanna R. Ferreira
    • 1
  • Guiomar N. Gomes
    • 1
  • Adriana C. Girardi
    • 2
  • Polliane M. Carvalho
    • 3
  • Fernando N. Nogueira
    • 3
  • Ruy R. Campos
    • 1
  • Cássia T. Bergamaschi
    • 1
  • Erika E. Nishi
    • 1
    • 4
    Email author
  1. 1.Department of Physiology, Escola Paulista de MedicinaUniversidade Federal de São Paulo - Escola Paulista de Medicina (UNIFESP-EPM)São PauloBrazil
  2. 2.Heart Institute (InCor)University of São Paulo Medical SchoolSão PauloBrazil
  3. 3.Department of Biomaterials and Oral Biology, Dentistry FacultyUniversidade de São PauloSão PauloBrazil
  4. 4.Cardiovascular and Respiratory Physiology Division, Department of PhysiologyUniversidade Federal de São Paulo - Escola Paulista de Medicina (UNIFESP-EPM)São PauloBrazil

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