Abstract
We recently showed that a substance P (SP)–dependent sympatho-inhibitory mechanism via afferent renal nerves is impaired in mesangioproliferative nephritis. Therefore, we tested the hypothesis that SP released from renal afferents inhibits the action potential (AP) production in their dorsal root ganglion (DRG) neurons. Cultured DRG neurons (Th11-L2) were investigated in current clamp mode to assess AP generation during both TRPV1 stimulation by protons (pH 6) and current injections with and without exposure to SP (0.5 µmol) or CGRP (0.5 µmol). Neurons were classified as tonic (sustained AP generation) or phasic (≤ 4 APs) upon current injection; voltage clamp experiments were performed for the investigation of TRPV1-mediated inward currents due to proton stimulation. Superfusion of renal neurons with protons and SP increased the number of action potentials in tonic neurons (9.6 ± 5 APs/10 s vs. 16.9 ± 6.1 APs/10 s, P < 0.05, mean ± SD, n = 7), while current injections with SP decreased it (15.2 ± 6 APs/600 ms vs. 10.2 ± 8 APs/600 ms, P < 0.05, mean ± SD, n = 29). Addition of SP significantly reduced acid-induced TRPV1-mediated currents in renal tonic neurons (− 518 ± 743 pA due to pH 6 superfusion vs. − 82 ± 50 pA due to pH 6 with SP superfusion). In conclusion, SP increased action potential production via a TRPV1-dependent mechanism in acid-sensitive renal neurons. On the other hand, current injection in the presence of SP led to decreased action potential production. Thus, the peptide SP modulates signaling pathways in renal neurons in an unexpected manner leading to both stimulation and inhibition of renal neuronal activity in different (e.g., acidic) environmental contexts.
Highlights
The publication of results of the SYMPLICITY 3 trial in 2015 [3] almost put an end to investigation of renal nerve ablation for the treatment of high blood pressure, The exact mechanisms by which the denervation of a single sympathetically innervated area, e.g., the kidney, leads to a decrease in arterial blood pressure with lower sympathetic central outflow are still not fully understood
The largest group of dorsal root ganglion (DRG) neurons under investigation was represented by medium-capacitance and medium-sized cells, as previously described [16]
When the neurons were stimulated with acidic solution that was directly applied via the multi-barrel perfusion pipette, the frequency of the acid-induced action potentials increased significantly in renal tonic neurons if exposed to substance P (SP) (Fig. 1; supplementary material: Section A)
Summary
The publication of results of the SYMPLICITY 3 trial in 2015 [3] almost put an end to investigation of renal nerve ablation for the treatment of high blood pressure, The exact mechanisms by which the denervation of a single sympathetically innervated area, e.g., the kidney, leads to a decrease in arterial blood pressure with lower sympathetic central outflow are still not fully understood. The main effect of the renal sympathetic system influences salt and water excretion [12]; so far no lasting physiological changes could be observed in hypertensive patients after renal denervation, which could explain blood pressure decreases after renal nerve ablation [43]. In this context, the afferent innervation to the kidney repeatedly came into focus [11, 12]. Even clinical studies suggest a role of afferent renal nerves in controlling the sympathetic nervous system [10, 26]. CGRP is a potent vasodilator released from peptidergic afferent nerve fibers, contributing to blood flow regulation [6, 45, 52] that will likely interfere with immune responses
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
