Interaction Of Afferent Renal Nerve Activity And Il-1R Signaling In Hypertension

Renal denervation was recently approved by the FDA for the treatment of hypertension, but the mechanism by which it reduces blood pressure is unclear. Studies of patients who have received the treatment have shown a variety of off-target improvements in conditions associated with sympathetic overactivity. One explanation is that these effects are due to ablation of sympathoexcitatory afferent renal nerves, which are overactive under conditions of renal inflammation. Renal interleukin 1-beta (IL-1β) is elevated in many cases of hypertension, as well as the DOCA-salt model of hypertension, and its activity may be responsible for the elevation in afferent renal nerve activity and arterial pressure. IL-1R activation increases the activity of afferent sensory nerves in other contexts. In these studies, I sought to determine if IL-1R activity was responsible for the increased afferent renal nerve activity characteristic of DOCA-salt hypertension. First, I characterized a mouse model of DOCA-salt hypertension and found that ablation of the afferent renal nerves attenuates hypertension in this model. Next, I used this model in combination with two methods of IL-1R disruption: genetic IL-1R knockout and pharmacological IL-1R antagonism. These methods attenuated hypertension in this model system. Further, combining either method with afferent renal denervation produced no additional attenuation of hypertension, and an acute depressor response to delivery of the IL-1R antagonist was observed only in animals with intact renal afferent nerves, indicating a common mechanism of action. In combination, these findings suggest that IL-1R activation is partially responsible for the elevated afferent renal nerve activity which stimulates central sympathetic outflow to renal and non-renal targets to drive DOCA-salt hypertension.

Author dc:creator

• Baumann, Daniel

• cytokines
• denervation
• hypertension
• kidney
• Neuromodulation

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/11299/263696

OAI identifier oai:identifier

oai:conservancy.umn.edu:11299/263696