Renal Afferent Nerve Modulation Of Sodium Homeostasis And Blood Pressure: A Sodium Sensitive Mechanism Countering The Development Of Salt‐Sensitive Hypertension?
Authors: Wainford Richard David , Walsh Kathryn Rose , Carmichael Casey Yumi 
Published: November 2023

AimWe have demonstrated a critical role of CNS Gαi2 proteins in sodium homeostasis and long‐term blood pressure regulation in response to acute or chronic sodium challenges in the Sprague‐Dawley rat. These studies tested the hypothesis that increased total body sodium activates the renal afferent nerves to evoke global and renal sympatho inhibition to facilitate sodium homeostasis and normotension, via a CNS signal transduction pathway involving Gαi2 proteins, in the Sprague‐Dawley rat.MethodsConscious Sprague‐Dawley rats, having undergone sham or renal afferent nerve denervation (Renal‐CAP; capsaicin 33 mM) underwent an IV volume expansion (VE; 5% BW), HR, MAP and natriuresis were continuously monitored (N=5/group). Radiotelemetred naïve, sham or Renal‐CAP treated Sprague‐Dawley rats were fed a 0.6% (NS) or 8% NaCl (HS) diet for 21 days and MAP was continuously monitored. On day‐21 plasma and renal NE content and PVN Gαi2 protein expression was determined. In naïve animals renal afferent nerve activity was assessed as NE‐evoked (1250 pmol) substance P (SP) release in a renal pelvis assay (N=5/group). Separate groups of naïve or Renal‐CAP treated rats were maintained on NS or HS and MAP and activity of the sodium chloride cotransporter (NCC) (peak natriuresis to iv hydrochlorothiazide (HCTZ; 2mg/kg infusion) was assessed on day‐21 (N=3/group).ResultsRemoval of the afferent renal nerves via Renal‐CAP significantly attenuated the natriuretic response to IV VE (peak UNaV [μeq/min]; Sham 43±4 vs Renal‐CAP 26±6, P<0.05) and evoked increased blood pressure (MAP 90‐min post‐VE [mmHg] Sham 118±3 vs Renal‐CAP 132±4, P<0.05). In naïve and sham surgical Sprague‐Dawley rats HS‐intake did not alter MAP and evoked suppression of plasma and renal NE (P<0.05) and increased PVN Gαi2 protein expression approximately 6‐fold (P<0.05). Further, in naïve rats HS‐evoked increased renal afferent nerve activity (assessed as SP release) (P<0.05). Removal of the renal afferent nerves immediately prior to HS‐intake, via Renal‐CAP surgery, evoked a rapid and persistent increase in MAP (P<0.05). In Renal‐CAP versus sham or naïve animals we observed significantly attenuated HS‐evoked global and renal specific sympathoinhibition (P<0.05) and the abolishment of PVN Gαi2 protein up regulation. In naïve normotensive animals HS‐evoked down regulation of NCC activity, Renal‐CAP evoked hypertension and abolished down regulation of NCC activity (peak UNaV to HCTZ [μeq/min] naïve NS 9.2±0.5, naïve HS 7.0±0.4, Renal‐CAP HS 10.3±0.8, P<0.05).ConclusionThe renal afferent nerves mediate natriuresis and blood pressure regulation during an acute challenge to fluid and electrolyte homeostasis in conscious Sprague‐Dawley rats. During chronic HS intake the renal afferent nerves function to prevent the development of salt‐sensitive hypertension. Our data suggests this occurs via a mechanism involving increased activity of the renal afferent nerves to potentiate central and renal sympathoinhibitory pathways, which involves up regulation of PVN Gαi2 proteins, to facilitate natriuresis in part via down regulation of NCC activity. These data suggest a novel role of the renal afferent nerves as a sodium‐sensitive mechanism that is critical for long‐term sodium homeostasis and blood pressure regulation.Support or Funding InformationNHLBI R01HL107330, K02HL1127182

Sprague‐Dawley Naïve
Sprague‐Dawley Sham Surgery
Sprague‐Dawley Renal‐CAP

NS
HS
NS
HS
NS
HS

Day‐21 MAP (mmHg)
103±3
107±2
106±3
108±2
105±3
120±2*τ

Plasma NE (nmol/L)
52±4
29±4*
58±5
26±3*
60±5
54±4τ

Renal NE (pg/mg)
598±24
375±39*
620±32
380±19*
606±28
541±32τ

PVN Gαi2 expression (ODU/mm2)
3.4±0.6
18.2±1.2*
2.9±0.7
17.4±0.9*
3.2±0.9
2.7±0.7τ

NE‐evoked Peak Δ in subtance P release (pg/ml)
14±2
22±3*
N.D.
N.D.
N.D.
N.D.

p<0.05 vs. respective NS group,
p<0.05 vs. respective Sham HS group value.