Abstract-Other than efferent sympathetic innervation, the kidney has peptidergic afferent fibers expressing TRPV1 receptors and releasing substance P. We tested the hypothesis that stimulation of afferent renal nerve activity with the TRPV1 agonist capsaicin inhibits efferent renal sympathetic nerve activity tonically by a neurokinin 1 receptordependant mechanism. Anesthetized Sprague-Dawley rats were instrumented as follows: (1) arterial and venous catheters for recording of blood pressure and heart rate and drug administration; (2) left-sided renal arterial catheter for selective intrarenal administration of the TRPV1 agonist capsaicin (3.3, 6.6, 10, 33*10 Ϫ7 M; 10 L; after 15, 30, 45, and 60 minutes, respectively) to stimulate afferent renal nerve activity; (3) right-sided bipolar electrode for continuous renal sympathetic nerve recording; and (4) specialized renal pelvic and renal artery catheters to separate pelvic from intrarenal afferent activity. Before and after intrarenal capsaicin application, increasing intravenous doses of the neurokinin 1 receptor blocker RP67580 were given. Intrarenal capsaicin decreased integrated renal sympathetic activity from 65.4Ϯ13.0 mV*s (baseline) to 12.8Ϯ3.2 mV*s (minimum; PϽ0.01). This sustained renal sympathetic inhibition reached its minimum within 70 minutes and was not directly linked to the transient electric afferent response to be expected with intrarenal capsaicin. Suppressed renal sympathetic activity transiently but completely recovered after intravenous administration of the neurokinin 1 blocker (maximum: 120.3Ϯ19.4 mV*s; PϽ0.01). Intrarenal afferent activity could be unequivocally separated from pelvic afferent activity. For the first time we provide direct evidence that afferent intrarenal nerves provide a tonically acting sympathoinhibitory system, which seems to be rather mediated by neurokinin release acting via neurokinin 1 receptor pathways rather than by electric afferent effects on central sympathetic outflow. Key Words: renal nerve Ⅲ afferent Ⅲ efferent Ⅲ TRPV1 Ⅲ NK 1 -receptor Ⅲ tonic inhibition T he kidney has a very complex sympathetic efferent and peptidergic afferent innervation 1 that recently became of increased interest as renal nerve ablation was introduced into the treatment of severely hypertensive patients. 2 However, especially the role of the afferent renal innervation in hypertension is still far from being fully understood. 3 We know that afferent renal nerve traffic is able to suppress the contralateral renal nerve activity by a sympathodepressory renorenal reflex that is altered in hypertension. 4 So far afferent nerve fibers involved in this reflex were said to be mainly projecting from the renal pelvis to the first neuron in the dorsal root ganglion, 5 although afferent nerve fibers are also found intrarenally in close vicinity to efferent sympathetic nerve fibers. 6 Furthermore, it is very likely that afferent nerve fibers are able to secrete transmitters, specifically substance P (SP) and calcitonin gene-related peptide (CGRP), ...
Freisinger W, Schatz J, Ditting T, Lampert A, Heinlein S, Lale N, Schmieder R, Veelken R. Sensory renal innervation: a kidney-specific firing activity due to a unique expression pattern of voltage-gated sodium channels? Am J Physiol Renal Physiol 304: F491-F497, 2013. First published January 2, 2013; doi:10.1152/ajprenal.00011.2012.-Sensory neurons with afferent axons from the kidney are extraordinary in their response to electrical stimulation. More than 50% exhibit a tonic firing pattern, i.e., sustained action potential firing throughout depolarizing, pointing to an increased excitability, whereas nonrenal neurons show mainly a phasic response, i.e., less than five action potentials. Here we investigated whether these peculiar firing characteristics of renal afferent neurons are due to differences in the expression of voltage-gated sodium channels (Na vs). Dorsal root ganglion (DRG) neurons from rats were recorded by the current-clamp technique and distinguished as "tonic" or "phasic. .67]; P Ͻ 0.05). These findings point to an increased presence of the TTX-resistant Na vs 1.8 and 1.9. Furthermore, tonic neurons exhibited a relatively higher portion of TTX-resistant sodium currents. Interestingly, mRNA expression of TTX-resistant sodium channels was significantly increased in renal, predominantly tonic, DRG neurons. Hence, under physiological conditions, renal sensory neurons exhibit predominantly a firing pattern associated with higher excitability. Our findings support that this is due to an increased expression and activation of TTX-resistant Na vs.
Recently, we showed that renal afferent neurons exhibit a unique firing pattern, i.e., predominantly sustained firing, upon stimulation. Pathological conditions such as renal inflammation likely alter excitability of renal afferent neurons. Here, we tested whether the proinflammatory chemokine CXCL1 alters the firing pattern of renal afferent neurons. Rat dorsal root ganglion neurons (Th11-L2), retrogradely labeled with dicarbocyanine dye, were incubated with CXCL1 (20 h) or vehicle before patchclamp recording. The firing pattern of neurons was characterized as tonic, i.e., sustained action potential (AP) firing, or phasic, i.e., Ͻ5 APs following current injection. Of the labeled renal afferents treated with vehicle, 58.9% exhibited a tonic firing pattern vs. 7.8%, in unlabeled, nonrenal neurons (P Ͻ 0.05). However, after exposure to CXCL1, significantly more phasic neurons were found among labeled renal neurons; hence the occurrence of tonic neurons with sustained firing upon electrical stimulation decreased (35.6 vs. 58.9%, P Ͻ 0.05). The firing frequency among tonic neurons was not statistically different between control and CXCL1-treated neurons. However, the lower firing frequency of phasic neurons was even further decreased with CXCL1 exposure [control: 1 AP/600 ms (1-2) vs. CXCL1: 1 AP/600 ms (1-1); P Ͻ 0.05; median (25th-75th percentile)]. Hence, CXCL1 shifted the firing pattern of renal afferents from a predominantly tonic to a more phasic firing pattern, suggesting that CXCL1 reduced the sensitivity of renal afferent units upon stimulation. chemokine; CXCL1; renal afferent nerve; voltage-gated sodium channel; tonic; phasic; firing pattern OBSERVATIONS IN PATIENTS with renal failure and/or hypertension who were nephrectomized (7, 17) strongly suggest that renal sensory afferent innervation increases sympathetic-mediated vasoconstriction. Moreover, sympathetic nerve activity in patients after renal transplantation was only normalized with concomitant bilateral nephrectomy (17). Additional work in experimental models indicated (21, 23) that efferent neurogenic influences on cardiac pathology in renal insufficiency are mediated by renal afferent nerve activity (1).In experimental animals, afferent innervation of the kidney was reported to contribute to the sustained blood pressure increases when renal structural damage was present (3, 46). In contrast, renal afferent nerves were described to act protectively against salt-sensitive hypertension and the structural renal damage of high blood pressure (24,44). A more recent study using a more selective method of renal afferent denervation suggests that this might not be the case, but it could be shown that selective renal afferent denervation was able to blunt the development of deoxycorticosterone acetate-salt hypertension (12).Therefore, the benefit of afferent renal nerve ablation for the treatment of refractory hypertension remains controversial (31). In any case, the modulatory influence of afferent renal nerves on sympathetic tone is not well understood....
Renal denervation (DNX) is a treatment for resistant arterial hypertension. Efferent sympathetic nerves regrow, but reinnervation by renal afferent nerves has only recently been shown in the renal pelvis of rats after unilateral DNX. We examined intrarenal perivascular afferent and sympathetic efferent nerves after unilateral surgical DNX. Tyrosine hydroxylase (TH), CGRP, and smooth muscle actin were identified in kidney sections from 12 Sprague-Dawley rats, to distinguish afferents, efferents, and vasculature. DNX kidneys and nondenervated kidneys were examined 1, 4, and 12 wk after DNX. Tissue levels of CGRP and norepinephrine (NE) were measured with ELISA and mass spectrometry, respectively. DNX decreased TH and CGRP labeling by 90% and 95%, respectively (P < 0.05) within 1 wk. After 12 wk TH and CGRP labeling returned to baseline with a shift toward afferent innervation (P < 0.05). Nondenervated kidneys showed a doubling of both labels within 12 wk (P < 0.05). CGRP content decreased by 72% [3.2 ± 0.3 vs. 0.9 ± 0.2 ng/gkidney; P < 0.05] and NA by 78% [1.1 ± 0.1 vs. 0.2 ± 0.1 pmol/mgkidney; P < 0.05] 1 wk after DNX. After 12 wk, CGRP, but not NE, content in DNX kidneys was fully recovered, with no changes in the nondenervated kidneys. The use of phenol in the DNX procedure did not influence this result. We found morphological reinnervation and transmitter recovery of afferents within 12 wk after DNX. Despite morphological evidence of sympathetic regrowth, NE content did not fully recover. These results suggest a long-term net surplus of afferent influence on the DNX kidney may be contributing to the blood pressure lowering effect of DNX.
Sympathetic efferent and peptidergic afferent renal nerves likely influence hypertensive and inflammatory kidney disease. Our recent investigation with confocal microscopy revealed that in the kidney sympathetic nerve endings are colocalized with afferent nerve fibers (Ditting T, Tiegs G, Rodionova K, Reeh PW, Neuhuber W, Freisinger W, Veelken R. Am J Physiol Renal Physiol 297: F1427-F1434, 2009; Veelken R, Vogel EM, Hilgers K, Amman K, Hartner A, Sass G, Neuhuber W, Tiegs G. J Am Soc Nephrol 19: 1371-1378, 2008). However, it is not known whether renal afferent nerves are influenced by sympathetic nerve activity. We tested the hypothesis that norepinephrine (NE) influences voltage-gated Ca(2+) channel currents in cultured renal dorsal root ganglion (DRG) neurons, i.e., the first-order neuron of the renal afferent pathway. DRG neurons (T11-L2) retrogradely labeled from the kidney and subsequently cultured, were investigated by whole-cell patch clamp. Voltage-gated calcium channels (VGCC) were investigated by voltage ramps (-100 to +80 mV, 300 ms, every 20 s). NE and appropriate adrenergic receptor antagonists were administered by microperfusion. NE (20 μM) reduced VGCC-mediated currents by 10.4 ± 3.0% (P < 0.01). This reduction was abolished by the α-adrenoreceptor inhibitor phentolamine and the α(2)-adrenoceptor antagonist yohimbine. The β-adrenoreceptor antagonist propranolol and the α(1)-adrenoceptor antagonist prazosin had no effect. The inhibitory effect of NE was abolished when N-type currents were blocked by ω-conotoxin GVIA, but was unaffected by other specific Ca(2+) channel inhibitors (ω-agatoxin IVA; nimodipine). Confocal microscopy revealed sympathetic innervation of DRGs and confirmed colocalization of afferent and efferent fibers within in the kidney. Hence NE released from intrarenal sympathetic nerve endings, or sympathetic fibers within the DRGs, or even circulating catecholamines, may influence the activity of peptidergic afferent nerve fibers through N-type Ca(2+) channels via an α(2)-adrenoceptor-dependent mechanism. However, the exact site and the functional role of this interaction remains to be elucidated.
Interventional renal ablation is a promising treatment procedure for therapy-resistant arterial hypertension. However, the underlying mechanisms are not completely understood: The efferent sympathetic renal nerves are known to play a key role in salt retention and renin release, but the role of the afferent nerves is not yet clearly defined, although strong evidence exists for a sympathoinhibitory function. It is widely accepted that there is some re-innervation of efferent sympathetic nerves after the denervation procedure, but re-innervation of afferent nerves is still doubted. Hence, we wanted to test the hypothesis that besides a sympathetic re-innervation a considerable afferent re-innervation occurs after renal denervation in rats. 50μm kidney slices from 12 male SD rats were stained for thyrosin hydroxylase (TH), calctonine gene related peptide (CGRP) and smooth muscle actin (SMA). Kidneys were examined 1, 4 and 12 weeks after left sided surgical renal denervation. The right innervated kidney served as control. Image stacks were generated using a confocal laser scanning microscope (0.5μm z-axis steps). Analysis of nerve density was done by 4 blinded investigators in 183 image stacks. Staining for TH (i.e. efferent) and CGRP (i.e. afferent) was visually scored (0-3). Stacks were visualized by Fiji Image J software. At week 1 both efferent [TH+] and afferent [CGRP+] fiber density was clearly reduced but was still detectable ([TH+]: right 2.43±0.10 vs. left 1.47±0.11; [CGRP+]: right 1.96±0.17 vs. left 0.86±0.12; P<0.001, each). After 4 weeks a clear-cut increase in nerve densities could be detected in the denervated kidneys, which further increased until week 12 ([TH+]: right 2.67±0.07 vs. left 2.35±0.12, P<0.03; [CGRP+]: right 2.06±0.16 vs. left 1.82±0.17, P=ns). Our study clearly indicates for the first time that there is not only a relevant sympathetic re-innervation but also a re-innervation of afferent nerves in the kidney. The afferent re-innervation process even seems to be more complete compared to sympathetic nerve fiber re-growth. Further studies have to be done to prove the functional relevance of our findings.
Renal sympathetic nerve activity (RSNA) is important in hypertension, volume disorders or renal disease. It is unclear if increases of RSNA in disease are due to sympathoexcitatory or impaired sympathoinhibitory renal afferent nerves. We present data from nephritic rats suggesting the latter.Nephritis due to OX7‐antibodies. Methohexital anesthetized nephritic rats & controls instrumented to stimulate renal afferent nerve activity (ARNA) in order to influence RSNA: ipsilateral renal arterial catheter for intrarenal administration (IRA) of the TRPV1 agonist capsaicin to stimulate ARNA (CAP 6.6*10‐7M) and induce release of the tachykinin receptor agonist SP from renal afferents; contralateral stainless steel electrode for RSNA recording; before and after IRA CAP the tachykinin‐receptor blocker RP67580 was given. Baseline RSNA & ARNA were assessed. Some nephritic rats pretreated with tachykinin receptor antagonists to prove increased SP effects.IRA CAP decreased RSNA from 67.5±12.0 µV*sec to 14.8±4.2 µV*sec (p<0.05) over 60 minutes while in nephritis RSNA suppression was abolished. Suppressed RSNA in controls was transiently reversed by the tachykinin inhibitor. Under resting conditions RSNA was higher, ARNA lower in nephritis as compared to controls. Tachykinreceptor antagonism ameliorated damage in renal nephritis suggesting increased SP release from renal afferent nerves despite lack of the tachykinin dependant sympathoinhibition seen in controls.Our data suggest that a tachykinin dependant reno‐sympathetic reflex mechanism exerts sympathoinhibitory effects being impaired under pathophysiological circumstances.
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