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Renal Denervation Prevents Immune Cell Activation and Renal Inflammation in Angiotensin II–Induced Hypertension
Open accessAbstract
Rationale: Inflammation and adaptive immunity play a crucial role in the development of hypertension. Angiotensin II and probably other hypertensive stimuli activate the central nervous system and promote T-cell activation and end-organ damage in peripheral tissues. Objective: To determine if renal sympathetic nerves mediate renal inflammation and T-cell activation in hypertension. Methods and Results: Bilateral renal denervation using phenol application to the renal arteries reduced renal norepinephrine levels and blunted angiotensin II–induced hypertension. Bilateral renal denervation also reduced inflammation, as reflected by decreased accumulation of total leukocytes, T cells, and both CD4 + and CD8 + T cells in the kidney. This was associated with a marked reduction in renal fibrosis, albuminuria, and nephrinuria. Unilateral renal denervation, which partly attenuated blood pressure, only reduced inflammation in the denervated kidney, suggesting that this effect is pressure independent. Angiotensin II also increased immunogenic isoketal-protein adducts in renal dendritic cells (DCs) and increased surface expression of costimulation markers and production of interleukin (IL)-1α, IL-1β, and IL-6 from splenic DCs. Norepinephrine also dose dependently stimulated isoketal formation in cultured DCs. Adoptive transfer of splenic DCs from angiotensin II–treated mice primed T-cell activation and hypertension in recipient mice. Renal denervation prevented these effects of hypertension on DCs. In contrast to these beneficial effects of ablating all renal nerves, renal afferent disruption with capsaicin had no effect on blood pressure or renal inflammation. Conclusions: Renal sympathetic nerves contribute to DC activation, subsequent T-cell infiltration and end-organ damage in the kidney in the development of hypertension.
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“Multiple preclinical studies have demonstrated that total RDN (TRDN, defined as ablation of the sympathetic efferent and sensory afferent nerves) causes a significant and sustained reduction in mean arterial blood pressure20,69–73.”
From Renal nerves in physiology, pathophysiology and interoception (2025) · cites this paper as [72]
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Citations
Cites
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Self-citationInflammation, Immunity, and Hypertension
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Self-citationJakubzick, C. V., Gautier, E., Gibbings, S. L., Sojka, D. K., Schlitzer, A., Johnson, T. E., Ivanov, S., Duan, Q., Bala, S., Condon, T., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.08.007 · Cited by 762
Catheter-Based Renal Sympathetic Denervation for Resistant Hypertension
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Predictors of blood pressure response in the SYMPLICITY HTN-3 trial
Kandzari, D. E., Bhatt, D. L., Brar, S. K., Devireddy, C. M., Esler, M., Fahy, M. P., Flack, J. M., Katzen, B. T., Lea, J. P., Lee, D. P., et al. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu441 · Cited by 552
DC isoketal-modified proteins activate T cells and promote hypertension
Kirabo, A., Fontana, V., de Faria, A. P., Loperena, R., Galindo, C. L., Wu, J., Bikineyeva, A. T., Dikalov, S., Xiao, L., Chen, W., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74084 · Cited by 549
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Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology
Forrester, S. J., Booz, G. W., Sigmund, C. D., Coffman, T. M., Kawai, T., Rizzo, V., Scalia, R. G., & Eguchi, S. (2018) · Physiological Reviews · doi:10.1152/physrev.00038.2017 · Cited by 1,135
Xiao, L., & Harrison, D. G. (2020) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2020.01.013 · Cited by 557
Self-citationImmune mechanisms of hypertension
Drummond, G. R., Vinh, A., Guzik, T. J., & Sobey, C. G. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-019-0160-5 · Cited by 447
The immunology of hypertension
Norlander, A. E., Madhur, M. S., & Harrison, D. G. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20171773 · Cited by 408
Self-citationRole of the Immune System in Hypertension
Rodríguez‐Iturbe, B., Pons, H., & Johnson, R. J. (2017) · Physiological Reviews · doi:10.1152/physrev.00031.2016 · Cited by 398
Metadata
- Authors
- Xiao, L., Kirabo, A., Wu, J., Saleh, M. A., Zhu, L., Wang, F., Takahashi, T., Loperena, R., Foss, J. D., Mernaugh, R. L., Chen, W., Roberts, J., Osborn, J. W., Itani, H. A., & Harrison, D. G.
- Affiliations
- University of Minnesota (US)
- ORCID
- Venue
- Circulation Research
- Published
- 2015-08-28
- Volume
- 117
- Issue
- 6
- Pages
- 547-557
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4629828
- OpenAlex
- W2166852030
- Cited by
- 233
- References
- 42
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 19 · 2023: 18 · 2022: 23 · 2021: 19 · 2020: 30 · 2019: 25 · 2018: 22 · 2017: 23 · 2016: 20 · 2015: 6
- FWCI
- 17.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Vanderbilt University
- Vanderbilt University Medical Center
- National Heart, Lung, and Blood Institute (R01HL039006, R01HL108701, K01HL130497, P01 HL58000, R01HL116476, F32HL124972, P01HL058000, HL039006, P01HL095070, R01HL105294, R01HL125865)
- National Institute of General Medical Sciences (GM015431, P50GM015431, P01GM015431, R25GM062459, T32GM007569)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079341)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Nephrology › Renal and Vascular Pathologies
- Keywords
- renal denervation, angiotensin II-induced hypertension, renal inflammation, T cell activation, renal sympathetic nerves, dendritic cells, norepinephrine, renal fibrosis, albuminuria, renal afferent nerves, capsaicin, adaptive immunity, interleukins
- MeSH terms
- Angiotensin II, Animals, Hypertension, Immunity, Cellular, Kidney, Mice, Inbred C57BL, Random Allocation, Sympathectomy, Mice, Knockout, Mice
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