Peptidergic afferent renal nerves (PARN) have been linked to kidney damage in hypertension and nephritis. Neither the receptors nor the signals controlling local release of neurokinines [calcitonin generelated peptide (CGRP) and substance P (SP)] and signal transmission to the brain are well-understood. We tested the hypothesis that PARN, compared with nonrenal afferents (Non-RN), are more sensitive to acidic stimulation via transient receptor potential vanilloid type 1 (TRPV1) channels and exhibit a distinctive firing pattern. PARN were distinguished from Non-RN by fluorescent labeling (DiI) and studied by in vitro patch-clamp techniques in dorsal root ganglion neurons (DRG; T11-L2). Acid-induced currents or firing due to current injection or acidic superfusion were studied in 252 neurons, harvested from 12 Sprague-Dawley rats. PARN showed higher acid-induced currents than Non-RN (transient: 15.9 Ϯ 5.1 vs. 0.4 Ϯ 0.2* pA/pF at pH 6; sustained: 20.0 Ϯ 4.5 vs. 6.2 Ϯ 1.2* pA/pF at pH 5; *P Ͻ 0.05). The TRPV1 antagonist capsazepine inhibited sustained, amiloride-transient currents. Forty-eight percent of PARN were classified as tonic neurons (TN ϭ sustained firing during current injection), and 52% were phasic (PN ϭ transient firing). Non-RN were rarely tonic (15%), but more frequently phasic (85%), than PARN (P Ͻ 0.001). TN were more frequently acid-sensitive than PN (50 -70 vs. 2-20%, P Ͻ 0.01). Furthermore, renal PN were more frequently acid-sensitive than nonrenal PN (20 vs. 2%, P Ͻ 0.01). Confocal microscopy revealed innervation of renal vessels, tubules, and glomeruli by CGRP-and partly SP-positive fibers coexpressing TRPV1. Our data show that PARN are represented by a very distinct population of small-tomedium sized DRG neurons exhibiting more frequently tonic firing and TRPV1-mediated acid sensitivity. These very distinct DRG neurons might play a pivotal role in renal physiology and disease.classification of neurons; capacitance; TRPV1 channels; ASIC; renal afferent nerve; rat NERVES CONTAINING NEUROPEPTIDES such as calcitonin gene-related peptide (CGRP) and substance P (SP) are important components of the sensory nervous system (13, 18). Although these afferent nerves until recently have been thought to sense stimuli in the periphery and transmit the information to the central nervous system, they also have an "efferent" local vasodilator function (10, 37). Acute administration of a CGRP receptor antagonist increases blood pressure in various models of hypertension, which indicates that this potent vasodilator plays a counterregulatory role to attenuate hypertension (12). Furthermore, CGRP was seen as nephroprotective in hypertensive kidney damage in other publications (3, 31). The release of neuronal peptides like CGRP is putatively dependent on the stimulation of transient receptor potential vanilloid type 1 (TRPV1) channels (30). But also in other organs, e.g., the liver, peptidergic afferent nerve fibers were able to release peptides to influence inflammatory and sclerotic processes (33). Hence, it is p...

Our observational pilot study in patients with CKD stages 3 and 4 indicates that treatment of hypertension with RDN decreases BP and slows or even halts the decline of renal function.

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), ...

Our data indicate that RDN may reduce office and 24-h ambulatory BP substantially in patients with moderate treatment-resistant hypertension. (Renal Denervation in Treatment Resistant Hypertension; NCT01687725).

Our data do not demonstrate any association between the presence of hypertension and antiretroviral therapy or immune status. However, hypertension seems to have a high impact on the existing risk for premature cardiovascular disease. Furthermore, overt proteinuria is frequent in HIV-1 infection with hypertension and might be due to hypertensive nephrosclerosis as well as yet undefined renal disease in these patients.