Abstract 032: Afferent Renal Denervation And IL-1 Receptor Blockade Attenuate The Pathogenesis Of Hypertension In DOCA-salt Mice Similarly: Evidence For A Common Mechanism?

Abstract

Emerging evidence suggests an interaction between renal inflammation and afferent renal nerves in some preclinical models of hypertension. In this study we tested the hypothesis that the inflammatory cytokine IL-1β interacts with afferent renal nerves in the pathogenesis of the DOCA-salt mouse model of hypertension. Specifically, we compared the effect of total renal denervation (TRDN) and afferent RDN (ARDN) on the development of DOCA-salt hypertension to that observed in animals receiving the IL-1 receptor antagonist anakinra. In the first study , 10-week-old male C57BL6/J mice were implanted with radiotelemeters for measurement of mean arterial pressure (MAP). DOCA was administered via subcutaneous pellet containing 50 mg of DOCA, controls received a drug free pellet. Uni-nephrectomy, pellet insertion, salt treatment, TRDN, ARDN, or sham denervation were all performed on the same day. TRDN and ARDN was performed through peri-axonal application of phenol and capsaicin respectively. In the second study , the IL-1 receptor antagonist anakinra (75mg/kg) or vehicle control (0.9% saline) was delivered via intraperitoneal injection daily 10 days post-induction of hypertension. Renal cytokine protein was quantified by Multiplex ELISA. All values reported are mean + SEM, all groups n=5. In the first study , MAP increased in sham treated DOCA-salt mice +43 ± 1 mmHg from baseline by the end of the 3 rd week of DOCA-salt. This response was attenuated by 40% in TRDN (+26 ± 4 mmHg) and by 44% in ARDN DOCA-salt mice (+24 ± 3 mmHg). IL-1β was increased in DOCA-salt kidneys (2.1 ± 0.4 pg/mg) compared to control kidneys (0.36 ± 0.1 pg/mg). In the second study , anakinra similarly attenuated the increase in MAP by 45% (+21 ± 2 mmHg) compared to vehicle controls (+38 ± 1 mmHg). Neither ARDN nor IL-1 receptor antagonism had any effect on renal inflammatory cytokines IL-1β, IL-6, or TNFα. The comparable attenuation in the MAP response to DOCA-salt ARDN and anakinra treated groups as well as the unchanged inflammatory phenotype is consistent with a common mechanism of action. We hypothesize that intrarenal IL-1β activates sympathoexcitatory renal afferent nerves to increase MAP in DOCA-salt mice. Future studies are needed to directly test this hypothesis.