Afferent renal denervation attenuates DOCA-salt hypertension in the mouse: Potential role of an IL-1β afferent renal nerve interaction.

Catheter based renal denervation (RDN) has emerged as a novel treatment for hypertension in patients. However, the mechanisms by which RDN lowers arterial pressure are unclear. We hypothesize that an interaction between afferent and efferent renal nerves and renal inflammation contributes to hypertension. Specifically, we hypothesized an interaction between afferent renal nerves and the inflammatory cytokine IL-1β contributes to the pathogenesis of hypertension in the DOCA-salt mouse. To test this hypothesis, we compared the effect of total RDN (TRDN), afferent RDN (ARDN) on pathogenesis DOCA-salt hypertension to that observed in IL-1R knockout mice. We also measured the effect of administration of the IL-1R antagonist anakinra on arterial pressure in DOCA-salt mice. 10-week-old male C57BL6/J mice were implanted with radio-telemetry probes in the carotid artery for measurement of arterial pressure. DOCA was administered via subcutaneous implantation of a silicon pellet containing 50 mg of DOCA. Sham mice received a drug free silicon pellet. Uni-nephrectomy, pellet insertion, salt treatment, TRDN or ARDN were all performed on the same day. TRDN was performed through surgical ablation and peri-axonal application of 10% phenol. ARDN was performed through peri-axonal application of capsaicin. IL-1R knockout mice and the IL-1R antagonist anakinra were used in two separate groups to suppress activation of IL-1R. Anakinra (75mg/kg) was delivered via intraperitoneal injection daily 10 days post induction of hypertension. Baseline arterial pressure was measured beginning 3 days prior to induction of DOCA-salt hypertension by radiotelemetry. Separate cohorts of mice were generated for protein quantification and histology, with urine and kidneys harvested 21 days post induction of DOCA-salt hypertension. Cytokine protein quantification was obtained through Multiplex ELISA. All values reported are mean + SEM. The mean arterial pressure (MAP) elevation in the sham treated DOCA-salt mice (+43 ± 1 mmHg increase from baseline during the 3rd week of the study) was attenuated by ~40% by TRDN (+25.9 ± 4 mmHg) and by ~44% in ARDN DOCA-salt mice (+24.1 ± 3 mmHg). Renal cytokines and chemokines were increased in DOCA-salt compared to sham treated mice. IL-1α and IL-1β were both increased in DOCA-salt kidneys (112.4 ± 19.2 pg/mg and 2.1 ± 0.4 pg/mg respectively) compared to sham kidneys (31.98 ± 4.4 pg/mg and 0.36 ± 0.06 pg/mg respectively). The DOCA-salt induced increase in MAP in IL-1R Knockout mice was similar to sham DOCA-salt mice (+39.1 ± 1 mmHg). In contrast, Anakinra treatment attenuated the increase in MAP similar to TRDN and ARDN mice (+22.4 ± 4 mmHg). The difference in outcome between the knockout and antagonist group suggests compensation by other inflammatory factors. The comparable attenuation in the MAP response to DOCA-salt ARDN and Anakinra treated groups is consistent with a common mechanism of action. We hypothesize that intrarenal IL-1b activates sympathoexcitatory renal afferent nerves to increase MAP in DOCA-salt mice. Future studies are needed to directly test this hypothesis. © FASEB.

Citation

Daniel C Baumann, Dusty Van Helden, Louise Evans, John W Osborn. Afferent renal denervation attenuates DOCA-salt hypertension in the mouse: Potential role of an IL-1β afferent renal nerve interaction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022 May;36 Suppl 1

PMID: 35554390

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