Neuronal Activation in the Central Nervous System of Rats in the Initial Stage of Chronic Kidney Disease-Modulatory Effects of Losartan and Moxonidine

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.

Cardiovascular Autonomic Dysfunction in Chronic Kidney Disease: a Comprehensive Review

“…Given the feasibility by which stress can be modified in CKD relative to other modifiable risk factors, more investigations are required to characterize the role of stress in driving CVD in CKD patients. Most recently, in 4/6 nephrectomized rats, Palkovits et al [132] demonstrated that CKD elicits high activity in several stressand pain-related brain regions, including the limbic system, hypothalamus, and circumventricular organs [132]. However, it remains to be determined whether stress-mediated activation of these brain regions promotes altered autonomic function in CKD and subsequent cardiovascular complications.…”

The interrelationship between cholinergic pathway in the magnocellular paraventricular nucleus and natriuresis

“…In line with these findings, a recent report has suggested that there is a close cross-talk between the kidney and CNS. Fos-activity of supraoptic and magnocellular PVN neurons is reduced in the chronic renal failure rats (Palkovits et al 2013). The involvement of the PVN in control of the kidney through the release of the antidiuretic hormone has been documented (Krowicki and Kapusta 2011).…”

Behavioral Changes During Development of Chronic Kidney Disease in Rats

“…Chronic kidney disease is frequently associated with neurological disorders affecting both peripheral and central nervous system resulting in behavioral abnormalities, including mental and cognitive dysfunctions (28)(29)(30). It has been shown that mild CKD may lead to activation of limbic system, central sympathetic, stress-and pain-related brain areas (31). Some CKD-related neurological complications have been attributed to impaired permeability of the blood-brain barrier (22,32,33), neuroinflammation, and oxidative stress (21)(22)(23).…”