Possible mechanism of subthalamic nucleus stimulation‐induced acute renal failure: A virally mediated transsynaptic tracing study in transgenic mouse model

The case report titled “acute renal failure in patients with bilateral deep brain stimulation” by Guimar~aes et al., indicated that effect of deep brain stimulation–subthalamic nucleus (DBS-STN) in hypothalamic centers remained a valid hypothesis which could explain an altered kidney function immediately after DBS-STN. Hypothalamic centers are well known to be important regions in the autonomic nervous system and have great significance for the emergence or maintenance of vascular tone and the release of vasopressin/ antidiuretic hormone. The retrograde transsynaptic tracer pseudorabies virus (PRV) has been widely used as a marker for multisynaptic connectivity in the brain. We would like to further complete the discussion of Guimar~aes et al. by using a virally mediated transsynaptic tracing study in the melanocortin-4 receptor (MC4R) green fluorescent protein (GFP) transgenic mouse model. Data from experiments in men and animal models have demonstrated that there is a close interaction between the kidney and the central nervous system. It is widely acknowledged that sympathetic influence in kidney functions is under control of hypothalamic nuclei. The melanocortin-4 receptor (MC4R) is expressed in numerous regions of brainstem and hypothalamus, and some findings indicated an important physiologic role for the MC4R in the regulation of renal sympathetic traffic by both leptin and insulin. We had characterized the projection from the kidney to STN and hypothalamic nuclei in an adult transgenic mouse line expressing GFP under the control of the MC4R promoter by using retrograde tracing techniques of PRV-614. We found that neurons expressing MC4R-GFP were distributed in STN and hypothalamic nuclei (Fig. 1), injections of PRV-614 into the kidney resulted in retrograde infection of neurons in STN and hypothalamic nuclei, PRV-614–infecting cells were most heavily concentrated in hypothalamic nuclei and distributed sparsely in STN, and most PRV-614–labeled cells specifically concentrated in the paraventricular hypothalamic nucleus (PVN). It was strikingly attractive that PRV-614/MC4R-GFP dual-labeled neurons were detected in the STN and PVN (Fig. 1), and PRV-614/tyrosine hydroxylase (TH), PRV-614/ tryptophan hydroxylase (TPH) dual-labeled neurons were detected in PVN (Fig. 1), not in STN, suggesting that different neuronal populations presented between the STN and PVN. Therefore, it was presumed that possible mechanism of the STN stimulation-induced acute renal failure involved between melanocortinergic, catecholaminergic, and serotonergic signals in hypothalamic centers, and melanocortinergic signals in STN. Because central regulation of sympathetic activity is a major component of melanocortinergic action and central serotonergic-positive and catecholaminergicpositive neurons participate in regulating sympathetic outflow, our data suggested that MC4R signaling between STN and hypothalamic nuclei involved in the sympathetic regulation of renal function. In conclusion, data presented here provided direct neuroanatomical evidence for the central melanocortin-sympathetic circuits from the STN and hypothalamic nuclei to the kidneys. Our observations strongly indicated that STN and hypothalamic nuclei was considered as a prominent neuronal circuit involved in the melanocortinergic regulation of renal function. Thereby, stimulation of STN may induce decreased renal blood flow (eg, secondary renal failure) by the central melanocortin-sympathetic mechanism. Further investigations will be required to research whether regional effects of DBSSTN on hypothalamic centers depend on the exact location of the contact in the STN area with a mouse model of STNDBS.