Abstract
The effect of mild chronic renal failure (CRF) induced by 4/6-nephrectomy (4/6NX) on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus). Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons) and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow) did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances.
Highlights
Patients with the most severe stage of chronic kidney disease or on maintenance hemodialysis are afflicted by remarkable cognitive deficits [1,2,3,4], enhanced perception of pain [5,6], sleep disturbances including sleep apnea [6,7] depression [8,9], and impaired quality of life [10]
Among the pathogenic factors involved in the disturbances of the central nervous system (CNS) enhanced blood levels of uremic neurotoxins [11], neurotoxic advanced glycation end products (AGEs) [12,13,14], homocysteine [15], asymmetric dimethylarginine (ADMA) [15,16], pro-inflammatory cytokines and reactive oxygen species (ROS), which are partly released from the damaged kidney (‘‘distant renal effects‘‘) play a role [17,18,19]
Since moxonidine is poorly soluble in water, solutions of both drugs were prepared by dilution of the appropriate amount of the substance in 10 ml of 0.9% NaCl, pH = 4.6, which was added to 990 ml of tap water
Summary
Patients with the most severe stage of chronic kidney disease (stage 5 CKD) or on maintenance hemodialysis are afflicted by remarkable cognitive deficits [1,2,3,4], enhanced perception of pain [5,6], sleep disturbances including sleep apnea [6,7] depression [8,9], and impaired quality of life [10]. Among the pathogenic factors involved in the disturbances of the central nervous system (CNS) enhanced blood levels of uremic neurotoxins (guanidino- and phenolic-compounds, indoxyl sulphate) [11], neurotoxic advanced glycation end products (AGEs) [12,13,14], homocysteine [15], asymmetric dimethylarginine (ADMA) [15,16], pro-inflammatory cytokines and reactive oxygen species (ROS), which are partly released from the damaged kidney (‘‘distant renal effects‘‘) play a role [17,18,19]. In CKD rats, the concentrations of norepinephrine in posterior hypothalamic nuclei and locus coeruleus (LC) are enhanced [22]. Rats with severe acute kidney injury display markedly elevated neuronal c-fos and Fra-2 immunoreactivities in the central biogenic amine cell groups, stress-sensitive forebrain areas/nuclei, central autonomic and neuronal cell groups involved in the regulation of fluid and electrolyte homeostasis [26]
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