Electrical stimulation of renal nerves for modulating urine glucose excretion in rats

Abstract

Background: The role of the kidney in glucose homeostasis has gained global interest. Kidneys are innervated by renal nerves, and renal denervation animal models have shown improved glucose regulation. We hypothesized that stimulation of renal nerves at kilohertz frequencies, which can block propagation of action potentials, would increase urine glucose excretion. Conversely, we hypothesized that low frequency stimulation, which has been shown to increase renal nerve activity, would decrease urine glucose excretion. Methods: We performed non-survival experiments on male rats under thiobutabarbital anesthesia. A cuff electrode was placed around the left renal artery, encircling the renal nerves. Ureters were cannulated bilaterally to obtain urine samples from each kidney independently for comparison. Renal nerves were stimulated at kilohertz frequencies (1-50 kHz) or low frequencies (2-5 Hz), with intravenous administration of a glucose bolus shortly into the 25-40-min stimulation period. Urine samples were collected at 5-10-min intervals, and colorimetric assays were used to quantify glucose excretion and concentration between stimulated and non-stimulated kidneys. A KruskalWallis test was performed across all stimulation frequencies (α = 0.05), followed by a post-hoc Wilcoxon rank sum test with Bonferroni correction (α = 0.005). Results: For kilohertz frequency trials, the stimulated kidney yielded a higher average total urine glucose excretion at 33 kHz (+ 24.5%; n = 9) than 1 kHz (− 5.9%; n = 6) and 50 kHz (+ 2.3%; n = 14). In low frequency stimulation trials, 5 Hz stimulation led to a lower average total urine glucose excretion (− 40.4%; n = 6) than 2 Hz (− 27.2%; n = 5). The average total urine glucose excretion between 33 kHz and 5 Hz was statistically significant (p < 0.005). Similar outcomes were observed for urine flow rate, which may suggest an associated response. No trends or statistical significance were observed for urine glucose concentrations. Conclusion: To our knowledge, this is the first study to investigate electrical stimulation of renal nerves to modulate urine glucose excretion. Our experimental results show that stimulation of renal nerves may modulate urine glucose excretion, however, this response may be associated with urine flow rate. Future work is needed to examine the underlying mechanisms and identify approaches for enhancing regulation of glucose excretion.

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“…Animal studies are often a necessary step to unravel the mechanisms of physiology leading to novel clinical applications in humans (figure 2). Animal experiments could also suggest a new field of BM application, as in the case of metabolic diseases [159,160]. Animal studies are also useful for investigating stimulus-evoked neural activity and the correlation between neural fibre-type activation and the related physiological effect [161,162].…”

“…Metabolic diseases are also related to the overactivation of the sympathetic nervous system, which leads to hypertension and insulin resistance, preliminary conditions for developing type 2 diabetes [197]. Several studies explored the possibility of suppressing sympathetic tone with stimulation to treat metabolism-related problems, as demonstrated in the case of renal nerve stimulation to control glucose excretion in urine in rats [160] and chronic CSN stimulation to restore insulin sensitivity and glucose tolerance in rats [159].…”

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“…In addition to the vagus nerve, studies on the regulatory role of other peripheral and CNS circuitries and the therapeutic usage of their modulation are considerably adding to progress in bioelectronic medicine ( Fig. 3; Talbot et al 2015;Guduru et al 2018;Güemes and Georgiou 2018;Jiman et al 2018;Kibleur and David 2018;Kovatchev 2018;Zhang et al 2018;Pavlov and Tracey 2019). These studies use methodological advances in material science, bioengineering, neuroscience, data analytics, computer modeling and mathematics, immunology, molecular biology, and other disciplines ( Fig.…”

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“…These findings may be of interest for further systematic investigations of the effects of VNS and its specific physiological effects (Qing et al, 2018). In addition to the vagus nerve, interesting research focusing on clinically-relevant physiological regulation of neural activity of other peripheral nerves was also published (Jiman et al, 2018). Previous findings have indicated that renal denervation has beneficial effects in treating drug-resistant hypertension (Pan et al, 2015).…”

“…There is also a growing interest in the role of the renal nerves in the regulation of glucose homeostasis (Pan et al, 2015). Using a cuff electrode positioned to modulate renal nerves residing adjacent to the left renal artery, Jiman et al (Jiman et al, 2018) reported that stimulation at kilohertz frequencies (1-50 kHz), designed to block action potential propagation, or low frequencies (2-5 Hz), with intravenous administration of a glucose, increased, or respectively lowered, urine glucose excretion (Jiman et al, 2018). This is an interesting avenue for organ-targeted neuromodulation studies aimed at altering glucose excretion for therapeutic benefit.…”