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Kopp UC. Neural control of Renal Function. San Rafael (CA): Morgan & Claypool Life Sciences; 2011.


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2.1. NEURAL PATHWAYS

Nerves moving fibers that operation to or indigenous the kidney are obtained from the celiac plexus and its subdivisions, lumbar splanchnic nerves (thoracolumbar paravertebral sympathetic trunk), and also the intermesenteric plexus (superior mesenteric ganglion). The celiac plexus is composed of the aorticorenal ganglion, the celiac ganglion, and also the significant splanchnic nerves. There are varieties differences in between the distribution between paravertebral (thoracic, lumbar) forgiveness chain ganglia and prevertebral celiac plexus ganglia. Vice versa, in the rat and also hamster, the majority of the cabinet bodies the renal postganglionic sorry fibers room localized in ipsilateral paravertebral forgiveness chain ganglia, in the cat and also monkey, just about half of the cell bodies of the postganglionic forgiveness fibers room localized top top the ipsilateral side. The renal sorry nerves originate native the intermediolateral pillar of the spinal cord indigenous T9 come T13. Number of nuclei in the brainstem task to intermediolateral column, including the medullary rapae nuclei, rostral ventrolateral medulla, A5 cabinet group, and also the paraventricular hypothalamic nucleus. Importantly, baroreceptor regulation of forgiveness outflow is regulated through rostral ventrolateral medulla, where different subgroups of neurons preferentially control sympathetic outflow to various organs, consisting of the kidney <58, 94>.

Analysis of the extrinsic renal nerve fibers, i.e., those close come the renal hilus, confirmed that the majority of the renal nerves are unmyelinated, 96% unmyelinated matches 4% myelinated in the rat <58>. The typical diameters of the unmyelinated and also myelinated renal nerve fibers space 1.3 and also 3.1 μM, respectively. A comparable distribution between unmyelinated and myelinated yarn was shown in the computer mouse <76>.


2.2. INTRARENAL circulation OF EFFERENT RENAL sympathetic NERVES

The nerves innervating the kidneys room either efferent or afferent nerves. The efferent nerves have from the neuraxis, i.e., para- and prevertebral ganglia, and also enter the hilus that the kidney follow me the renal artery and vein. The afferent renal nerves take trip from the kidney towards the dorsal source ganglia along the spinal cord. The an initial part of this publication will focus on the efferent renal innervation. The afferent renal innervation the the kidney and their role in the water and salt homeostasis will certainly be debated toward the finish of the book. The efferent renal nerves are postganglionic, and also the majority of these space adrenergic, i.e., they contain norepinephrine varicosities at your nerve terminals. An essential neurotransmitter role for norepinephrine was supported by the observations that decreasing renal forgiveness nerve task to zero through chronic renal denervation lessened renal organization norepinephrine concentration by >95% <16, 64>. Conversely, raising renal forgiveness nerve activity by renal forgiveness nerve stimulation raised norepinephrine concentration in renal venous blood <27, 135, 193>. There is no proof for parasympathetic innervation that the kidney.

The efferent sorry renal nerves are dispersed to every segments of the intrarenal vasculature in the renal cortex and also outer medulla, consisting of the interlobar, arcuate, and also interlobular arteries and also the afferent and also efferent glomerular arterioles. Over there are couple of sympathetic nerves in the inside medulla. The the renal vasculature, the highest possible innervation has been observed along the afferent glomerular arterioles followed by the efferent glomerular arterioles <4, 11> (Figure 2.1).


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FIGURE 2.1

Sympathetic nerve yarn (N), established with one antibody versus tyrosine hydroxylase, are situated along the afferent and efferent arteriole close to the glomerulus (G).


As the afferent arterioles approach the glomerulus, the phenotype the the vascular smooth muscle cells alters to dense cored granules. These space the granular cells of the juxtaglomerular apparatus which contain renin. Over there is clear proof for these cells to it is in innervated by sympathetic nerves <5>.

Likewise, all parts of the nephron space innervated by forgiveness nerves <6–10> (Figure 2.2). Direct renal tubular innervation has actually been prove in miscellaneous species, including man. There is a synaptic contact in between renal sympathetic nerve fiber varicosities and renal tubular epithelial cabinet basolateral membranes. Quantitative analysis of the distribution and density the neuroeffector junctions confirmed that the biggest numbers the neuroeffector junctions room in the proximal tubule adhered to by the special ascending body of Henle"s loop, the distal convoluted tubule, and the collecting duct. As to density (i.e., number of innervated tubular profiles/number of tubular profiles examined), this was greatest in the thick ascending body of Henle"s loop, adhered to by the distal convoluted tubule, the proximal tubule, and the collecting duct <7>.


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FIGURE 2.2

Sympathetic nerves terminals are nearby to the basolateral membrane the the tubules. Shown are nerve varicosities (N) containing neurotransmitter motor (v) close to a proximal tubule (PT) (left panel) and a cortical collecting duct (CCD) (right panel) (more...)


There is a regional distribution the the renal innervation from outer cortex to inner medulla. The level of efferent renal forgiveness innervation is best at the corticomedullary border and also decreases in the superficial cortical region and in the deeper regions of the medulla. An ext recent studies have additionally identified forgiveness nerves in the renal pelvic wall <149> (Figure 2.3).


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FIGURE 2.3

Sympathetic nerve yarn (arrows), established with an antibody versus the norepinephrine transporter (NE-t) space located amongst the smooth muscle fibers in the renal pelvic wall.


Ultrastructural studies have identified two types of axons innervating vessels and renal tubules the the rabbit and rat kidney <175, 186>. Form I has constant microtubules v the varicosities, whereas kind II does not. The range of the diameter of form I and kind II axons does not overlap, which argues the crucial hypothesis the they subserve different renal functions. In assistance of this hypothesis, it has actually been observed within the rabbit kidney that kind I and kind II axons space differentially distributed among the miscellaneous neuroeffectors. The distribution of type I axons is higher on afferent 보다 efferent glomerular arterioles, juxtaglomerular cells, and also proximal tubular cells. The thickness of kind II axons on afferent arterioles, being much less than the of form I axons, is similar to the on efferent arterioles, juxtaglomerular cells, and proximal tubular cells. In this context, it is of attention that research studies in rats showed that although most effectors, i.e., renal vasculature, juxtaglomerular cells, and also nephrons, space innervated by separate nerve fibers, i.e., the renal nerves synapsing v only among them, over there is proof for the same nerve yarn synapsing with much more than one effector <58>.


2.3. Attributes OF THE EFFERENT RENAL sympathetic NERVE SIGNALS

It is crucial to identify that most recordings the efferent renal forgiveness nerve activity (ERSNA) are derived from multifiber preparations, i beg your pardon consist the numerous single nerve fibers. Return the firing frequency in each single nerve fiber is quite low, large numbers of fibers might fire at the same time causing discharges of synthetic spikes that can be an ext easily recorded. Among the most characteristic functions of ERSNA is that pulse synchronous discharges mediated to a huge extent by activation the the arterial baroreceptors. However, the is important to note that no each cardiac cycle needs to be linked with a explode of ERSNA activity.

In anesthetized animals, measurements of multifiber ERSNA is accomplished by record an magnified signal indigenous an electrode placed about the central portion the a reduced renal nerve bundle. In mindful animals, renal nerve task is videotaped from one electrode placed approximately intact nerve (i.e., no cut). Thus, this recordings stand for both ERSNA and afferent renal nerve task (ARNA). However, in most basal conditions, these recordings most likely represent ERSNA because of the much reduced ARNA versus ERSNA in the nonstressed mindful state. For evident reasons, comparable techniques because that assessing renal nerve task cannot be used in humans. Instead, forgiveness nerve task to various organs, consisting of the kidney, have the right to be estimated by measure up norepinephrine spillover native a specific organ into plasma. Throughout infusion of a tiny amount the tritiated norepinephrine, norepinephrine concentration is measure up in venous outflow native the organ, e.g., the kidney, in addition to organ plasma flow. Norepinephrine spillover native the kidney is measure up by isotope dilution: <(CV − CA) + CAE> × renal plasma flow, whereby CV and also CA stand for norepinephrine concentration in renal venous and also arterial plasma, respectively, and E the fractional exploit of tritiated norepinephrine by the kidney <71>. The is crucial to note that urinary norepinephrine concentration shows plasma norepinephrine concentration <135> and also is for this reason not a great estimate that ERSNA.

Studies the the effects of boosts in ERSNA top top renal duty have most commonly used electrical square-wave signal at different intensities and also frequencies via electrodes placed approximately the peripheral part of one renal nerve bundle. Plenty of studies have presented that this method results in frequency-dependent transforms in renin secretion, urinary salt excretion, and also renal blood (Figure 1.1), the same, similar thing those elicited by reflex renal nerve stimulation and also thus suggesting that this method mimics physiological alters in ERSNA. However, evaluation of the ERSNA signal would suggest that a more physiological signal would be a diamond-shaped signal <62>, with the amplitude that the an initial and last spikes in every burst being smaller sized than those in the middle of the burst. Also, these bursts are not of continuous frequency and also amplitude since ERSNA is under tonic regulate of the central nervous system. Utilizing digital methods to build stimulus trends that reproduced multifiber ERSNA, i.e., the diamond-shaped signal, the alters in renal blood flow and also urinary sodium excretion developed by electric stimulation making use of the diamond-wave sample were compared with those developed by the square-wave pattern. The two different signals were matched because that total incorporated voltage. Interestingly, renal nerve stimulation through the diamond-wave pattern features resulted in better decreases in renal blood flow and also urinary sodium excretion 보다 nerve stimulation through the square-wave qualities (Figure 2.4). Among the feasible contributors to the much more enhanced functional responses to the diamond-wave stimulation might be the intermittent character of the diamond-shaped signal. In ~ the same number of pulses/s, intermittent renal nerve stimulation produces greater renal vascular responses contrasted to continuous stimulation. The longer the rest period between bursts, the better the renal vascular response. These data argued that the enhanced rest time raised the time for feasible repletion the the neurotransmitter in ~ the renal forgiveness nerve terminals minimizing possible exhaustion of neurotransmitter relax mechanisms. Bring away together, these studies suggested that electric renal nerve stimulation utilizing a more physiological stimulation pattern produces greater impacts on both the renal vasculature and also tubules 보다 renal nerve stimulation using the more commonly provided square-wave pattern.


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FIGURE 2.4

Comparing the results of diamond- vs square-wave stimuli on (A) renal blood flow (RBF) and also (B) urinary sodium excretion verified that the reduce in renal blood flow and also urinary sodium excretion in an answer to renal nerve stimulation were higher with (more...)


2.4. NEUROTRANSMITTERS

As discussed above, there is solid evidence for the primary neurotransmitter released by the renal sorry nerves gift norepinephrine. Surgical removal that the renal nerves results in marked reduction the renal organization norepinephrine content (>90%), and stimulation the the renal nerves boosts renal venous outflow of norepinephrine <16, 27, 64, 135>. Norepinephrine exerts various impacts on renal duty by activation of α- and β-adrenoceptors (vide infra). Norepinephrine is synthesized in neural organization from the amino acid tyrosine. Tyrosine is converted right into L-DOPA (3,4-dihydroxy-L-phenylalanine) through tyrosine hydroxylase. This is the rate-limiting step. L-DOPA is decarboxylated come dopamine by fragrant acid decarboxylase. Dopamine is converted to norepinephrine through dopamine β hydroxylase (Figure 2.5). Norepinephrine is transported into synaptic vesicles in the nerve terminals indigenous which it is eventually released and acts upon presynaptic and also postsynaptic adrenoceptors.


There is anatomical evidence for the presence of neuropeptide Y (NPY) in renal forgiveness nerves the is co-released v norepinephrine during increases in ERSNA <58>. However, the physiological duty for NPY in the manage of renal role is still unclear. Back NPY is current in most sympathetic nerves innervating the renal vasculature and also renal tubules, the high-intensity renal nerve stimulation compelled to relax NPY raises the concern of the physiological definition of NPY in these nerve terminals. Other cofactors released during activation of the renal sorry nerves space the purine and pyridine nucleotides, the most significant of which is ATP. Interestingly, in comparison to NPY, research studies in secluded rat and mouse kidneys display that ATP contributes come the vasoconstrictor responses come renal sympathetic nerve stimulation at relatively low frequencies <222, 243>. In addition, the existence of purinergic P2 receptor on principal and intercalated cells of the collecting duct close to neural varicosities suggests that ATP may add to neurally induced salt reabsorption <174, 243>. However, the useful importance of these receptors is at this time unclear.

Although there is solid proof for dopamine receptor in renal tissue, over there is no evidence for neural release of dopamine, together none that the renal functional responses to renal sympathetic nerve stimulation is impacted by dopamine receptor antagonists <58, 262>. The bulk of intrarenal dopamine is synthesized native circulating L-DOPA by the proximal convoluted tubule and also released locally to exert its actions in a paracrine and autocrine fashion. Basal circulating levels of dopamine are too low to stimulate dopamine receptors on renal vascular tissue. However, there is considerable evidence because that circulating dopamine raising urinary salt excretion, that is natriuretic action being intensified in conditions of high salt dietary intake.

Although acetylcholinesterase has been found in renal tissue, over there is little evidence because that cholinergic nerves in the kidney. The renal functional results of renal sorry nerve stimulation room not influenced by cholinergic antagonists. However, the existence of tubular acetylcholinesterase says that acetylcholine have the right to be synthesized in the kidney from circulating choline.


2.5. ADRENOCEPTORS

As stated above, the primary neurotransmitter in forgiveness nerves is norepinephrine, which acts upon the renal vasculature, renal tubules, and also the juxtaglomerular cells to reason renal vasoconstriction, sodium reabsorption, and also increased renin cheap rate, respectively, by activation the a selection of adrenoceptors (Figure 2.6). The adrenoceptors originally established as α- and also β-adrenoceptors have subsequently been further classified in a variety of subtypes following numerous pharmacological and also molecular biological studies. There are α1- and α2-adrenoceptors and also β1-, β2-, and also β3-adrenoceptors. In addition, assorted α1 and also α2 subtypes have been identified and are referred to as α1A-, α1B-, and α1D-adrenoceptors and also α2A-, α2B-, and also α2C-adrenoceptors, respectively. The various adrenoceptor subtypes space G-protein-coupled receptors. The binding that the ligand, norepinephrine, come its receptor elicits a signaling cascade entailing various intracellular messengers dependent upon which adrenoceptor subtype is activated.


FIGURE 2.6

The major effects of increases in renal sorry nerve activity involve rises in renin secretion price by activation of β1-adrenoceptors, to reduce in urinary sodium excretion through activation that α1B-adrenoceptors, and also decreases in (more...)


Although with various affinities, all 3 subtypes that the α1-adrenoceptors space coupled to the Gq/11 protein pathway resulting in activation the phospholipase C (PLC), which consequently leads to boosted intracellular calcium and activation of protein kinase C (PKC). Activation that PKC may connect with the phospholipase A2/arachidonic mountain intracellular cascade leading to development of eicosanoids <102, 247>. Furthermore, activation of α1-adrenoceptors may likewise activate the MAP kinase pathway, which over a longer time structure determines the rate of growth and also hypertrophy the the vascular smooth muscle cells <248>. The circulation of the assorted α1 subtype adrenoceptors in the kidney varies. α1A- and also α1B-adrenoceptors space equally distributed in the cortex and also outer strip of the medulla, whereas the α1B-adrenoceptor subtype predominates in the inner stripe of the medulla <78>. Most studies would suggest that the renal vasoconstrictor responses come norepinephrine are mainly mediated by activation that α1A-adrenoceptors through activation that α1B-adrenoceptors playing a lesser role. Activation that α1B-adrenoceptors is assumed to pat a greater duty in the results of norepinephrine top top tubular salt reabsorption. The norepinephrine-mediated activation of α1-adrenoceptors top top the vascular smooth muscle cells causes a contraction that rises both afferent and also efferent arteriolar resistance, i beg your pardon will alleviate renal blood flow and also glomerular filtration rate; the magnitude of contraction is dependence on the level the renal sympathetic nerve activation <58>. Concerning the duty for α1D-adrenoceptors, researches in bladder organization may show a role for α1D-adrenoceptors in mediating the activation the mechanosensitive nerves <116> in the renal pelvic area (vide infra).

All the the α2-subtype adrenoceptors space coupled come Gi/o protein <102, 247> resulting in inhibition of adenylyl cyclase, the N-type calcium (Ca++) voltage channel and/or activation that the G-protein-coupled inwardly rectifying K networks <22, 209, 242>. Stimulation the α2A- and also α2C-adrenoceptors ~ above the presynaptic nerve terminals leads to decreases in norepinephrine release, one import negative feedback mechanism affiliated in controlling norepinephrine relax from sorry nerve terminals. Norepinephrine is reported to have greater affinity because that α2C-adrenoceptors, which room activated by lower action potential frequencies <102, 209>. Furthermore, there are studies which indicate that activation of α2B-adrenoceptors, situated on vascular smooth muscle cells, boosts arterial push <209>.

Regarding the tubular effects developed by boosts in ERSNA, there is substantial evidence for α1-adrenoceptors, located on the basolateral next of the tubular cells, regulation sodium and water reabsorption. Many of the research studies have concentrated on the proximal tubules where catecholamines are uncovered to wake up basolateral membrane Na+/K+-ATPase <2>, the primary mechanism pumping salt out the the cabinet <87>. The concomitant entrance of salt from the tubular lumen throughout the apical membrane right into the epithelial cell is brought out by the sodium–hydrogen exchanger (NHE3), whose task is boosted by catecholamine stimulation of α1A- and also α1B-adrenoceptors <168, 169>. NHE3 embedded in the apical membrane the proximal tubule epithelial cells is a vital protein identify the price of sodium entry right into the cabinet and, hence, in its entirety tubular liquid reabsorption. Acute elevations in renal perfusion pressure reason a relocation that the NHE3 protein come the subapical region, regular with a reduction in proximal tubular liquid reabsorption. By contrast, obstacles that cause an increased renal forgiveness nerve task are associated with boosted insertion of NHE3 in the main locations of the microvilli to enhance fluid reabsorption. As yet, proof for a direct action of the renal sympathetic nerves top top the circulation of NHE3 has not to be forthcoming.

Further under the nephron, i.e., in the distal tubule and collecting duct, α2-adrenoceptors space the primary subtype <206, 208>. As debated above, activation of these adrenoceptors leads to reduced activation that adenylyl cyclase and also thus cAMP generation. The main effects of activation of this receptors show up to it is in to reduce/buffer the impacts of other agents, e.g., the antidiuretic hormone and PGE2 <208>, i m sorry are well-known to activate the adenylyl cyclase/cAMP/protein kinase A pathway. Furthermore, there space reports that indicate that activation that α-adrenoceptors, maybe α2-adrenoceptors, reduce Na/K/2Cl protein expression in the special ascending limb. These research studies may explain that the α2-adrenoceptor mediated to reduce in Cl− flux in this tubular segment. What is at this time not recognized is even if it is the norepinephrine-mediated decrease in Cl− flux is a straight effect or requires the involvement of various other factors, consisting of nitric oxide (NO) <210>.

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β1-adrenoceptors are current in high thickness on the renin-containing juxtaglomerular cells in the afferent arterioles <58>. Stimulation of this receptors outcomes in increased activity of adenylyl cyclase bring about activation of the cAMP/PKA transduction cascade ultimately resulting in raised renin secretion rate, the size of which is dependence on the intensity of ERSNA <120, 133>. β2-adrenoceptors have actually been localized come the collecting ducts, and also they also use cAMP together a 2nd messenger system. Their function at this website is unclear.