Interdependent Regulation of Afferent Renal Nerve Activity and Renal Function: Role of Transient Receptor Potential Vanilloid Type 1, Neurokinin 1, and Calcitonin Gene-Related Peptide Receptors

Abstract

Our previous studies have shown that the activation of the transient receptor potential vanilloid type 1 (TRPV1) expressed in the renal pelvis leads to an increase in ipsilateral afferent renal nerve activity (ARNA) and contralateral renal excretory function, but the molecular mechanisms of TRPV1 action are largely unknown. This study tests the hypothesis that activation of receptors of neurokinin 1 (NK1) or calcitonin gene-related peptide (CGRP) by endogenously released substance P (SP) or CGRP following TRPV1 activation, respectively, governs TRPV1-induced increases in ARNA and renal excretory function. Capsaicin (CAP; 0.04, 0.4, and 4 nM), a selective TRPV1 agonist, administered into the renal pelvis dose-dependently increased ARNA. CAP (4 nM)-induced increases in ipsilateral ARNA or contralateral urine flow rate (Uflow) and urinary sodium excretion (UNa) were abolished by capsazepine (CAPZ), a selective TRPV1 antagonist, or 2-[1-imino-2-(2-antagonists, but not by CGRP8-37, a selective CGRP receptor antagonist. Both SP (7.4 nM) and CGRP (0.13 M) increased ARNA, Uflow, or UNa, and increases in these parameters induced by CGRP but not SP were abolished by CAPZ. CAP at 4 nM perfused into the renal pelvis caused the release of SP and CGRP, which was blocked by CAPZ but not by RP67580, L703,606, or CGRP8-37. Immunofluorescence results showed that NK1 receptors were expressed in sensory neurons in dorsal root ganglion and sensory nerve fibers innervating the renal pelvis. Taken together, our data indicate that NK1 activation induced by SP release upon TRPV1 activation governs TRPV1 function and that a TRPV1-dependent mechanism is operant in CGRP action.The transient receptor potential vanilloid type 1 (TRPV1) channel is a nonselective cation channel that can be activated by capsaicin (CAP), noxious heat, lipid metabolites, and protons (Guo et al., 1999;Julius and Basbaum, 2001;Klionsky et al., 2006). Our previous data show that activation of TRPV1 by CAP perfused into the unilateral renal pelvis leads to bilateral diuresis and natriuresis via a dual renorenal reflex and that this effect is abolished after ipsilateral renal denervation (Zhu et al., 2005). Moreover, hypertonic saline perfused into the renal pelvis causes increases in ipsilateral afferent renal nerve activity (ARNA) and contralateral renal excretory function by activation of TRPV1 and neurokinin 1 (NK1) receptors (Zhu et al., 2007). These data indicate that TRPV1-positive sensory nerves innervating the renal pelvis play an important role in regulating ARNA and maintaining sodium and water homeostasis, but the mechanism by whichTRPV1 activation induces elevated ARNA is largely unknown.Activation of TRPV1 expressed in sensory nerves of unmyelinated C-fibers or thinly myelinated A␦-fibers causes release of a variety of sensory neuropeptides, including substance P (SP) and calcitonin gene-related peptide (CGRP). SP and CGRP are colocalized in renal pelvis sensory nerves and may be totally depleted after CAP treatment (Hua et al., 1987). CGRP perfu...

Effects of a High-Salt Diet on TRPV-1-Dependent Renal Nerve Activity in Dahl Salt-Sensitive Rats

“…As described previously [6,23], 50 mg·kg –1 pentobarbital sodium was administrated intraperitoneally for anesthesia for the recording of mean arterial pressure (MAP), ARNA with or without drug perfusion into the renal pelvis, and urine collection from the ureters (see detail in supplement). Renal nerves were isolated via a left flank incision and placed on the stainless steel electrode for the recording of multifiber nerve activity (see detail in supplement).…”

“…TRPV1 may be activated by multiple chemical and physical stimuli including vanilloid compounds, noxious heat, lipid metabolites, NaCl and protons [4,5]. It has been shown that activation of TRPV1 expressed in the renal pelvis leads to increases in afferent renal nerve activity (ARNA), renal sodium and water excretion, and the release of substance P (SP) and calcitonin gene-related peptide (CGRP) [6]. While TRPV1-induced increases in ARNA and renal excretory function are governed by activation of the neurokinin receptor 1 (NK1) by SP released from renal afferent nerves, CGRP-induced enhancement in ARNA and renal excretory function appears to be attributed to TRPV1 activation [6].…”

“…In the kidney, TRPV1-positive sensory nerves heavily innervate the tubules of the renal cortex and medulla, renal pelvis, pelvi-ureteric junction and ureter, with these fibers being found between the layers of smooth muscle and epithelia in the renal pelvis [7,16]. Activation of TRPV1 expressed in these sensory nerves leads to the release of sensory neuropeptides including SP and CGRP that may possess profound effects on the kidney and cardiovascular tissues in regulating sodium and water homeostasis and blood pressure [6,16,17,18,19,20]. …”

“…It has been shown that activation of TRPV1 expressed in the renal pelvis leads to increases in afferent renal nerve activity (ARNA), renal sodium and water excretion, and the release of substance P (SP) and calcitonin gene-related peptide (CGRP) [6]. While TRPV1-induced increases in ARNA and renal excretory function are governed by activation of the neurokinin receptor 1 (NK1) by SP released from renal afferent nerves, CGRP-induced enhancement in ARNA and renal excretory function appears to be attributed to TRPV1 activation [6]. Results from single nerve fiber recording confirm that enhancement in ARNA induced by capsaicin (CAP), a selective TRPV1 agonist, perfused into the renal pelvis can be abolished not only by capsazepine, a selective TRPV1 antagonist, but also by L-703,606, a selective NK1 receptor antagonist, indicating that NK1 receptor activation plays a key role in mediating TRPV1-induced increases in ARNA [7].…”

Transient Receptor Potential Vanilloid Type 1 Receptors in Hypertensive Renal Damage

“…Although the exact role of the afferent fibers and their local effects in kidney tissue remains to be defined, Xie et al 7 have recently studied the putative cross-talk between TRPV1 receptors SP and CGRP in the renal pelvis. Activation of TRPV1 receptors in the renal pelvis by capsaicin induces an increase in ipsilateral afferent renal nerve activity and in contralateral renal excretory function.…”