IL-1R mediated renal sensory nerve activity drives hypertension in the DOCA-Salt mouse

Abstract

Clinical trials of renal denervation (RDN) have shown unanticipated changes in non-renal sympathetic activity. It has been hypothesized that this is due to ablation of sympathoexcitatory afferent renal nerves, which are overactive under conditions of renal inflammation. This study sought to investigate the interaction of the inflammatory cytokine, IL-1, and afferent renal nerves in the pathogenesis of hypertension. To test this hypothesis, we compared the effect of afferent RDN (ARDN) to the administration of the IL-1R antagonist anakinra, on the pathogenesis DOCA-salt hypertension. In addition, the combination of ARDN and anakinra treatments in DOCA-salt mice was administered to assess the degree of mechanistic overlap. 10-week-old male C57BL6/J mice were implanted with radio-telemetry probes in the carotid artery for measurement of mean arterial pressure (MAP). 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, ARDN were all performed or started on the same day. ARDN was performed through peri-axonal application of capsaicin. IL-1R antagonist anakinra was used to suppress activation of IL-1R. Anakinra (75mg/kg) was delivered via intraperitoneal injection daily 10 days post induction of hypertension. Animals in the untreated or monotherapy groups received sham RDN and/or vehicle injections. Baseline MAP was measured 3 days prior to induction of DOCA-salt hypertension by radiotelemetry. MAP increased in untreated DOCA-salt mice by 42 ± 2 mmHg (n=7) from baseline in the final week of the study. In comparison, this response was attenuated by 42% by ARDN (+24 ± 2 mmHg, n=7). 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 of MAP in mice treated with anakinra alone (+23 ± 3 mmHg, n=9), or the combination of ARDN and anakinra (+26 ± 3 mmHg, n=5) was similar to ARDN monotherapy (+24 ± 2 mmHg, n=7). All treatment groups showed statistically significant changes in MAP compared to the SHAM and Vehicle treated group with 2 Way ANOVA and Tukey test for multiple comparisons. The finding that ARDN and anakinra combination therapy provides no additional benefit beyond ARDN or anakinra alone, suggests a common mechanism. We propose that antagonism of IL-1R blocks IL-1 mediated activation of afferent renal nerves resulting in decreased central sympathetic tone and decreased MAP. Further investigation into the mechanisms of cytokine mediated sensory fiber activation in the kidney are the subject of ongoing studies. T32DK083250-01A1, R01HL116476 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.