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| Year : 2007 | Volume
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| Issue : 4 | Page : 512-522 |
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| Nephrotic Proteinuria and the Autonomic Nervous System |
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Marcello Camici
Internal Medicine Department, Pisa University, Italy
Click here for correspondence address and email
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 Abstract | | |
Nephrotic proteinuria triggers off complex neuro-endocrine mechanisms where forebrain activation results in sympathetic over activity. An attempt is made to discuss and analyze the renal sympathetic efferent nerve hyperactivity, the role played by the angiotensin/nitric oxide system during proteinuria and the nitric oxide/angiotensin imbalance in the hypothalamus. Several questions arise: further experimental and clinical studies are necessary. The answers to these questions may disclose new clinical and therapeutic perspectives for the nephrotic syndrome. Keywords: Brain, Proteinuria, Nephrotic Edema, Sympathetic Over activity
How to cite this article:
Camici M. Nephrotic Proteinuria and the Autonomic Nervous System. Saudi J Kidney Dis Transpl 2007;18:512-22 |
| Introduction | |  |
Both the over fill and under fill hypotheses of nephrotic edema, emphasize the importance of circulatory plasma volume (filling) as the main pathogenetic mechanism for edema genesis [Figure - 1].[1],[2] In the under fill theory, secondary renal sodium retention develops to compensate circulatory volume contraction (circulatory under filling), whereas in over fill theory, the abnormality leading to nephrotic edema is a primary renal sodium retention and consequent plasma volume expansion (circulatory over filling): a unifying hypothesis has been also proposed. [3],[4],[5]
Maintenance of physiologically constant extra cellular osmolarity and sodium concentration depends on a precise balance between intake and excretion of sodium and water (body sodium and volume homeostasis). The kidney plays a key role not only in the physiologic maintenance of body sodium and water homeostasis but also during edematous states such as the nephrotic syndrome (NS). In sodium-retaining disorders, extra-renal mechanisms such as neuro-endocrine manifesttations are also important.
Variations in the composition of blood plasma are picked up in the brain by the small areas that lack a blood-brain barrier. These areas, the circumventricular organs, surround the ventricular system. Three of these are involved in body fluid homeostasis: the subfornical organ (SFO), organum vasculosum laminae terminalis (OVLT), both of which are located in the anteroventral third ventricle, and the area postrema (AP), which is located at the transition of the fourth ventricle and the central canal of spinal cord.[6],[7] Increases in the effective osmolality of plasma are known to activate neurons in the OVLT[8] and, lesions of the OVLT markedly attenuate the stimulation of thirst and neurohypophyseal secretion of vasopressin (VP) and oxytocin (OT) by hyperosmolality in rats,[9] thus indicating the importance of the forebrain in mediating these adaptive responses.
How important is the forebrain activation by autonomic nervous system into the course of nephrotic edema? The purpose of this article is to provide new insights about body sodium/volume homeostasis and neuro-endocrine mechanisms during nephrotic proteinuria: it is useful to consider the neuro-endocrine manifestations of the NS in terms of their peripheral versus central origins. After nephrotic proteinuria, a number of vasoactive and neuro-active humural factors are released;[10],[11] angiotensin II, cytokines, nitric oxide (NO) and sympathetic nervous system activation. The present article is focused on the new insights about potential underlying mechanisms by which the above neuroactive humoral factors may contribute to the pathogenesis of nephrotic edema.
| Sympathetic Nervous System and the Kidney | | |
The kidneys have a dense afferent sensory and efferent sympathetic innervation. Neural sympathetic control of the kidney is at the level of the vessels, the tubules and the juxtaglomerular cells. [12],[13] In experimental studies, by using electrical stimulation to the efferent renal sympathetic nerves at frequencies just below the threshold for causing a decrease in renal blood flow, it was shown that a reversible decrease in urinary sodium excretion occurred in the absence of changes in glomerular filtration rate, renal blood flow and arterial pressure. [14]
Additional experiments demonstrated that this effect occurred in the proximal convoluted tubule, the thick ascending limb of Henle's loop, the distal convoluted tubule and the collecting duct and was caused by the release of norepinephrine from renal sympathetic nerve terminals with stimulation of post-synaptic alpha 1 adreno-receptors.[15],[16],[17]
Functionally specific renal sympathetic nerve fibers regulate the functions of tubules, renal blood vessels and juxtaglomerular granular cells; [12] increase in renal sympathetic nerve activity (RSNA) produces increase in renin secretion rate, decrease in urinary sodium excretion by increasing renal tubular sodium reabsorption and decreasing renal blood flow [Figure - 2]. This differentiated regulation occurs via mechanisms that operate at multiple sites within the classic reflex arc: peripherally at the level of afferent input stimuli (sympathetic inflow) to various reflex pathways, centrally at the level of interconnecttions between various central neuron pools and peripherally at the level of efferent fibers (sympathetic outflow) targeted at various effectors within the organ.
Therefore, this reflex arc can be origin as well as target of averactivity of SNS. Afferent signals from the diseased kidney are transmitted to the vasomotor control center in the forebrain and efferent signals of sympathoexcitation may operate in the kidney. In the forebrain (hypothalamus), afferent inhibittory and excitatory reflex activity may be modulated by endocrine and paracrine factors such as angiotensin II and NO.[18],[19],[20],[21]
| Sympathetic Nervous System and Nephrotic Proteinuria | | |
Increased noradrenaline secretion rates have been observed in patients with the NS and normal glomerular filtration rate. [22] In experimental NS, Aman and [23] colleagues showed that peripherally and centrally active sympatholytic drugs, significantly attenuate proteinuria in rats subtotally nephrectomized: this indicates that inhibition of sympathetic nerve activity (SNA) by itself is of structural and functional benefit in proteinuria. The exact mechanism involved in direct damage of the kidney by sympathetic activity has not been resolved. In many proteinuric renal diseases, podocyte injury is the first step in development of proteinuria: [24] adrenergic receptors seem to be present on podocytes, because adrenergic agonists can induce both calcium influx and ATP release which in turn can induce proliferation, at least in vitro. [25],[26] This direct effect of cathecolamines may lead to podocyte injury independent of their hemodynamic effects. In normotensive diabetic humans, moxonidine (sympathoplegic agent) reduces albuminuria without affecting blood pressure. [27]
In rats with nephrotic edema, one of the mechanisms that contributes to the increased renal sodium retention is an increased renal sympathetic nerve activity (RSNA)[17],[28] and this RSNA is dependent, in large part, on increased efferent RSNA. [29] In nephrotic rats, the cardiopulmonary baroreflex inhibition of efferent RSNA is decreased; the defect lies in the central portion of the reflex and this may contribute to the observed increase in efferent RSNA of nephrotic edema. [30],[31] The central neurons system alterations underlying this cardiac baroreflex defect have not been defined.
| Angiotensin II and Cardiac Baroreflex Modulation in Nephrotic Proteinuria | | |
In rats, physiologic alterations in endogenous angiotensin II (AGII) activity tonically influence basal level of peripheral RSNA and its cardiac baroreflex regulation;[20],[32] this interaction between RSNA and renin-angiotensin system have a key role in the control of renal function and may be peripheral (renal) and/or central (nervous system). [33] Intrarenal interaction may be at renal synaptic nerve terminals (presynaptic) where AGII has an important presynaptic action to facilitate and to optimize the release of norepinephrine from renal sympathetic nerve terminals as well as from the central nervous system (activity mediated by AGII-type A receptors). [34],[35] In experimental studies, the effects of increased renal sympathetic nerve activity on renal function are attenuated when the activity of renin angiotensin system is suppressed or antagonized with ACE inhibitors or AGIItype AT1 receptor antagonists and the effects on intrarenal administration of AGII are atenuated after renal denervation.[36],[37],[38] In humans, administration of angiotensin converting enzyme inhibitor (enalpril) and antagonist of AGII-type A1 receptor (losartan) reduces sympathetic hyperactivity in patients with chronic renal failure. [39]
Extrarenal interaction may be in the hypothalamus at the level of the normal circuit, that mediates baroreceptor control of sympathetic vasomotor outflow, the so-called circumventricular organs. They consist of the subfornical organ, organum vasculosum of the lamina terminalis, median eminence and area postrema, which seem to be major sites of action of circulating AGII in the CNS.[40],[41]
In rabbits and rats, AT1 receptors are localized to areas of the brain that are exposed to blood-borne AGII, such as the circumventricular organs, including the SFO, median eminence, vascular organ of the lamina terminalis, anterior pituitary and area postrema in the hind brain.[42],[43] Not only circulating AGII, but also AGII of CNS origin may interact with SNS and it seems that there is a differential modulation of baroreflex control by neuron-versus glia-derived AG II. [32] The precise nature by which brain AGII participates in the regulation of sympathetic outflow is still not completely understood; firstly because the physiologic central neural circuit mediating baroreceptor reflex is not clearly known, [44] secondly because the basic physiologic autocrine, paracrine and endocrine effects of AGII are not completely understood [45] and thirdly because the molecular basis of arterial baroreceptor mechanotransduction is poorly understood. [46] What are the factors that link AT2 subtype AGII receptor, AGIII-AGIV fragments, epithelial sodium channels subunits (ENaC) and modulation of sympathetic tone inside neuronal tissue? In AT2-receptor "knockout" mice, deletion of AT2 receptor gene results in raised blood pressure and enhanced sensitivity to the receptor effects of AGII. [47] This suggests that the AT2 receptor mediates a vasodepressor effect and may functionally oppose the effects mediated by the AT1 receptor, possibly via bradykinin and nitric oxide (NO). [48] In human adult, AT2 receptors are present in the brain, heart, adrenal medulla, kidney and reproducetive tissues [Figure - 3]: [49] in the human brain, AGII receptor have been identified and characterized. [50],[51]
What is the link between AT2 subtype AGII receptors expression in neuronal forebrain tissue and, increased RSNA in nephrotic edema? While most interest has focused on forebrain circumventricular actions, areas of the brainstem such as the nucleus of the solitary tract and the ventrolateral medulla contain high concentrations of AT1 receptors: activetion of these receptors acutely incrases RSNA and RSNA baroreflex responses.[52]
| Role of Nitric Oxide in Angiotensin-induced Cardiac Baroreflex Depression and Increased Efferent Renal Sympathetic Nerve Activity in Nephrotic Proteinuria | | |
Cardiac baroreflex depression
Adenoviral vector demonstrates that AGII-induced depression of the cardiac baroreflex is mediated by NO released by endothelial NO synthase (eNOS or NOS III) in the nucleus tractus solitarii (NTS) of the rat. [53] Importantly, this action of AGII is mediated by NO itself, rather thanperoxynitrate, because adenoviral over expression of catalase, an enzyme that destroyes reactive oxygen species, did not affect the action of AGII in the NTS: [54] peroxynitrate is a product of the reaction between NO and superoxide, may affect release of transmitters (such as glutamate, GABA and achetylcoline) independent of NO. [55] In experimental models, central infusion of AGII has been shown to decrease neuronal NOS gene expression in the brainstem [56] (NTS; the brainstem termination site for baroreceptor afferents). Among direct vascular effects of angiotensin, there is the activation of nicotinamide-adeninedinucleotide phosphate oxidase (vascular NADPHase) and generation of superoxide anions,[57],[58] with oxygen-radical induced degradation of NO: [59] there is a subsequent decreased NO bioactivity. So, a first hypothetical explanation for cardiac baroreflex depression in the NS may be an increase in oxidative stress in the hypothalamus (brainstem) caused by AGII via cerebral vascular smooth muscle NADPH oxidase activation ([Figure - 4], Hypotheses A).
NO is a ubiquitous messenger molecule, which is involved in regulation of numerous biological functions. It is produced from stereospecific oxidation of L-arginine by a family of enzymes known as NO-synthase (NOS) (nNOS: neuronal NOS or NOS I; iNOS: inducible NOS or NOS II; eNOS: endothelial NOS or NOSIII. [60] NO is well recognized as an endogenous neuro-transmitter, neuro-mudulator and inter and intracellular messenger for signalling transduction. It has become clear that endogenous NO might be implicated in control of heart rate, acting at multiple sites including visceral afferents,[61] brainstem neurons that mediate cardiovascular reflexes,[62] cardiac and renal autonomic ganglia.[63],[64],[65],[66],[67],[68],[69] Thus, a second hypothetical explanation for cardiac baroreflex depression in the NS may be activation in the nucleus tracti solitarii (NTS) by AGIItype 1 receptor (AT1) of vascular cerebral eNOS and subsequent NO diffusion outside cerebral vascular system to nearby GABA ergic- NTS inter-neurons to enhance inhibition of neurons mediating the baroreceptor reflex in the NTS [70] ([Figure - 4] Hypotheses B).
Efferent RSNA increase
How can we link the decrease in cardiopulmonary baroreflex inhibition of efferent RSNA to the subsequent increase in efferent RSNA[29],[30],[31] and what is the explanation?
NO is a neurotransmitter at synapses in autonomic ganglia in peripheral nervous system: [71] NO produced by nNOS in proximity to the neuro-effector junction potentiates vagal transmission and decreases sympathetic transmission.[72],[73] The NO system is a natural anatgonist of cathecolamines. In rats, chronic PAN-induced NS results in down regulation of kidney iNOS and nNOS, vascular iNOS and brain nNOS: [74] so, it is possible that a reduction of NO as neurotransmitter occurs in close proximity to the neuro-effector junctions, with subsequent increase in renal sympathetic nerve activity. The down regulation of kidney iNOS and nNOS in chronic PAN-induced nephrotic rats seems to be linked to the proteinuria itself. [74]
This situation has been explored in experimental models. In chronic PAN-induced NS rats, proteinuria by itself seems to down regulate kidney iNOS and nNOS with subsequent deficiency of NO neurotransmission bioactivity and imbalance in renal parasympathetic/sympathetic activity [74] ([Figure - 5], kidney autonomic peripheral nervous system).
When the natural action of NO is reduced, normal or even low activity of the sympathetic nervous system can become detrimental for the kidney because of an imbalance between parasympathetic and sympathetic nervous system (autonomic dysfunction). This principle is already known for AGII. [75] An example is renal ablation. This model is associated with down regulation of iNOS and eNOS in the remnant kidney. [76]
Concluding Remarks
The autonomic nervous system plays an important physiologic role in the control of renal functions. In sodium- retaining disorders, such as the NS, there is over activity of the sympathetic nervous system and dysfunction of classic reflex autonomic arc: cardiac baroreflex depression and increased RSNA are expressions of this dysfunction.Clinical and experimental observations show that proteinuria is not merely a marker of chronic nephropathies but is also involved in the progression to end stage renal failure.After nephrotic proteinuria, forebrain (hypothalamus) activation is revealed by sympathetic hyperactivity, dependent in large part, on angiotensin II-induced cardiac baroreflex depression at forebrain level.
What is the role played by NO in this depression? What is the role of angiotensin peptides and their receptors? Will modulation of angiotensin/nitric oxide system at forebrain level influence the NS? These and related questions are fertile grounds for future studies in experimental NS.
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Correspondence Address:
Marcello Camici
Internal Medicine Department, Pisa University
Italy
 Source of Support: None, Conflict of Interest: None  | Check |
PMID: 17951936 
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5] |
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