Abstract
To examine if brain neurons involved in the efferent control of the kidneys possess melanocortin-4 receptor (MC4-R) and/or tryptophan hydroxylase (TPH). Retrograde tracing pseudorabies virus (PRV)-614 was injected into the kidneys in adult male MC4R-green fluorescent protein (GFP) transgenic mice. After a survival time of 3-7 days, spinal cord and brain were removed and sectioned, and processed for PRV-614 visualization. The neurochemical phenotype of PRV-614-positive neurons was identified using double or triple immunocytochemical labeling against PRV-614, MC4R, or TPH. Double and triple labeling was quantified using microscopy. The majority of PRV-614 immunopositive neurons which also expressed immunoreactivity for MC4R were located in the ipsilateral intermediolateral cell column (IML) of the thoracic spinal cord, the paraventricular nucleus (PVN) of the hypothalamus, and raphe pallidus (RPa), nucleus raphe magnus (NRM) and ventromedial medulla (VMM) of the brainstem. Triple-labeled MC4R/PRV-614/TPH neurons were concentrated in the PVN, RPa, NRM and VMM. These data strongly suggest that central MC4R and TPH are involved in the efferent neuronal control of the kidneys.
Highlights
As an important determinant of balancing the volume and composition of body fluids, the kidneys play a critical role in the homeostatic control of water and sodium [1,2,3], and understanding the mechanisms of their central control could lead to pharmacological and behavioral therapeutic tools of renal-related disease, e.g. renal hypertension and renal diabetes
At 4 days after kidney injection (n = 3, phase II), pseudorabies virus (PRV)-614 immunopositive neurons were detected in the brainstem (e.g., rostral ventrolateral medulla (RVLM), A5 noradrenergic cell region (A5) and nucleus of the solitary tract (NTS), Figure 2) and the paraventricular nucleus of the hypothalamus (PVN) that give rise to direct descending projections to intermediolateral cell column (IML) of the thoracic spinal cord
PRV-614 retrogradely labeled neurons were found in numerous CNS regions [43, 45, 50, 52], but the proportion of these neurons possessing melanocortin-4 receptor (MC4R)-green fluorescent protein (GFP) were mainly located in IML of the thoracic spinal cord, the PVN of the hypothalamus, and raphe pallidus (RPa), nucleus raphe magnus (NRM) and ventromedial medulla (VMM)
Summary
As an important determinant of balancing the volume and composition of body fluids, the kidneys play a critical role in the homeostatic control of water and sodium [1,2,3], and understanding the mechanisms of their central control could lead to pharmacological and behavioral therapeutic tools of renal-related disease, e.g. renal hypertension and renal diabetes. Many other sensory, metabolic, and emotional factors influence renal sympathetic activity or induce the change of renal function, suggesting that between brain and kidneys comprise a complex neural circuit that integrates multiple signals relevant for this change. It has been evidenced that the central melanocortin system plays an important role in the regulation of basal plasma insulin levels and glucose tolerance [28,29,30,31,32]. A growing body of literature supports that sympathetic activity are tightly interconnected via hypothalamic melanocortinergic pathways involving the melanocortin-4 receptor (MC4R), a G protein-coupled, seven-transmembrane receptor expressed in the brain [15, 33,34,35]. The main objective of this study is to provide direct neuroanatomical evidence for the central melanocortin circuits connecting to renal tissues via autonomic nervous system
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