Renal Afferent Nerve Activation and Arterial Pressure Control: Role of Inflammatory Cytokines in Hypertension
Authors: Banek Christopher , Osborn John 
Published: April 2020

Neural control of the kidney as well as aberrant renal nerve signaling remain a primary focus of research in cardiovascular and renal disease, including hypertension. Recent preclinical reports employing targeted afferent renal nerve ablation have confirmed the central role for afferent renal nerves in the development of hypertension, including studies in the DOCA‐salt rat. Moreover, direct measurement of afferent renal nerve activity (ARNA) in DOCA‐salt rats revealed elevated tonic ARNA; however, the mechanisms contributing to the increased ARNA, and in turn hypertension, remain unaddressed. Renal inflammation is postulated to be a primary contributor to the aberrant ARNA in this model, due to the elevated pro‐inflammatory cytokines (IL‐1β, IL‐6, TNFα, MCP‐1, GRO/KC) present in the DOCA‐salt kidneys. Therefore, we aimed to directly test the role of these cytokines in modulating ARNA and concomitant cardiovascular responses in normotensive and DOCA‐salt rats. We hypothesized intrarenal inflammatory cytokine administration would increase ARNA and arterial pressure (AP) in both treatment groups.

To interrogate this hypothesis, unilateral nephrectomized male Sprague Dawley rats (300–350g; n=16) were administered 100mg DOCA (s.c.) or silicone vehicle (n=8/group), followed by 3vweeks of high salt diet administered through drinking water (0.9% NaCl). Each animal then underwent an acute surgical preparation under isoflurane anesthesia (2%) to record AP, heart rate (HR), and ARNA responses to randomized intrarenal injection (10μL; 0.1 μg/μL) of the following cytokines: IL‐1β, IL‐6, TNFα, MCP‐1, GRO/KC, and 0.9% saline (VEH). ARNA responses were normalized to maximal afferent activation (%Amax) achieved by TRPV1‐agonist (capsaicin; 50μM) injection at end of protocol. Responses between and within treatment groups were analyzed by a repeated‐measures two‐way ANOVA (α=.05). Data presented as mean ± SEM. * p<.05 vs. Vehicle; # p<.05 vs. Saline.

Prior to stimulation, baseline ARNA (4.9 ± 1.3 vs. 13.8 ± 2.1 %Amax) and AP (106 ± 2 vs. *151 ± 5 mmHg) were elevated in DOCA rats vs. vehicle controls. Compared to VEH responses, no changes from baseline ARNA, AP or HR responses were detected following IL‐1β, TNFα, MCP‐1, or GRO/KC injection. Compared to saline vehicle, IL‐6 injection produced an increase in ARNA in both VEH (5.9 ± 1.8 vs. #24.1 ± 5.4 %Amax) and DOCA rats (14.7 ± 2.2 vs. #24.1 ± 5.4 %Amax). Interestingly, AP decreased following IL‐6 injection in parallel to ARNA stimulation in VEH (1 ± 1 vs. −6 ± 2mmHg) and DOCA (0 ± 1 vs. −11 ± 4mmHg) compared to saline. No differences in responses between DOCA and VEH were detected.

To summarize, IL‐6 injection increased ARNA in both VEH and DOCA supported our hypothesis; however, the corresponding depressor responses did not. Together, we conclude IL‐6 is a direct activator of ARNA independent of DOCA. Several studies have previously reported a depressor response following ARNA activation under anesthesia, so the central processing of ARNA may be altered under anesthesia compared to the conscious state, which is a limitation of this study. Current dose‐response studies and conscious preparations are underway to elucidate this important cardio‐renal‐neural axis in blood pressure homeostasis.

Support or Funding Information

NIH R00HL141650 (CTB); R01HL116476 (JWO)