The role of the mechanosensitive renal sensory afferent nerve sympathoinhibitory reno‐renal reflex in sympathetic outflow, natriuresis, and blood pressure regulation

Abstract

AimWe hypothesize that challenges to sodium homeostasis activate the sensory afferent renal nerve reno‐renal reflex, by either direct mechanical or chemical stimulation, to evoke sympathoinhibition, sodium homeostasis and normotension in the Sprague‐Dawley (SD) rat.MethodsConscious male SD rats fed a 0.6% NaCl diet underwent an acute IV volume expansion (VE; 5% BW) or IV sodium load (2h 1M NaCl Infusion – constant infusion volume) 10‐days post sham (S) or afferent renal nerve ablation (Renal‐CAP; capsaicin 33 mM) and HR, MAP, natriuresis (UNaV) and PVN neuronal activation (c‐Fos expression via IHC) were assessed (N=4/group). Groups of naïve male SD rats were fed a normal (0.6%, NS) or high salt (4% NaCl, HS) diet for 21 days and afferent renal nerve activity was assessed as 1) norepinephrine (NE) (1250 pmol) and NaCl‐evoked (450mM) substance P (SP) release in an ex vivo renal pelvic assay or 2) natriuresis to increased renal pelvic pressure across a physiological range (2.5–10 mmHg) (mechanical stimulus) or a 450mM NaCl infusion (chemical stimulus) in anesthetized rats (N=4/group). Radiotelemetered male (M) and female (F) SD rats underwent S or Renal‐CAP immediately prior to a 21‐day NS or HS diet. MAP was monitored continuously and on day‐21 plasma and renal NE content were assessed (N=5/group).ResultsRenal‐CAP attenuated the natriuretic and PVN parvocellular responses to IV VE (peak UNaV [μeq/min]; S 43±4 vs Renal‐CAP 26±6, P<0.05, PVN Medial Parvocellular neuronal activation [c‐fos positive cells]; S 49±6 vs Renal‐CAP 22±5 P<0.05) in M SD rats. In contrast Renal‐CAP did not alter these responses to IV 1M NaCl (peak UNaV [μeq/min]; S 21±4 vs Renal‐CAP 21±3, PVN Medial Parvocellular neuronal activation [c‐fos positive cells]; S 57±5vs Renal‐CAP 60±7). In an ex vivo renal pelvis preparation we observed increased NE, but not NaCl, mediated afferent renal nerve activity (NE‐evoked peak ΔSP [ng/ml); NS 14±2, HS 22±3, P<0.05, NaCl‐evoked peak ΔSP [ng/ml]; NS 17±3, HS 16±2) in M SD rats. In anesthetized M SD rats, we observed enhanced natriuresis to increased renal pelvic pressure (10mmHg pelvic pressure UNaV [μeq/min]; NS 1.8±0.4 vs HS 4.3±0.6, P<0.05) following HS intake. We observed no effect of increased pelvic NaCl levels on natriuresis. In naïve M SD rats HS‐intake did not alter MAP and evoked suppression of plasma and renal NE (P<0.05). Renal‐CAP immediately prior to HS‐intake persistently increased MAP in M and F SD rats (Day 21 MAP [mmHg] S HS 103±3, Renal‐CAP HS 124±4, P<0.05) and attenuated HS‐evoked global and renal sympathoinhibition (P<0.05).ConclusionThe sensory mechanosensitive, but not chemosensitive, afferent renal nerves mediate acute activation of PVN sympathoinhibitory neurons to activate the sympathoinhibitory reno‐renal reflex to facilitate natriuresis. During HS intake the renal afferent nerves counter the development of salt‐sensitive hypertension via a mechanism involving increased mechanosensitive afferent nerve responsiveness to suppress sympathetic outflow and maintain normotension. These studies provide new mechanistic insight into the actions of the sensory afferent renal nerves in sodium homeostasis and blood pressure regulation and have potential implications for the therapeutic application of renal nerve ablation in human subjects.Support or Funding InformationThis work was supported by NIH grants R01HL107330 and K02HL112718 and AHA 16MM32090001 to RDW and T32GM008541 to AAF