Review

Targeting neural reflex circuits in immunity to treat kidney disease

  • Nature Reviews Nephrology 13, 669680 (2017)
  • doi:10.1038/nrneph.2017.132
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Abstract

Neural pathways regulate immunity and inflammation via the inflammatory reflex and specific molecular targets can be modulated by stimulating neurons. Neuroimmunomodulation by nonpharmacological methods is emerging as a novel therapeutic strategy for inflammatory diseases, including kidney diseases and hypertension. Electrical stimulation of vagus neurons or treatment with pulsed ultrasound activates the cholinergic anti-inflammatory pathway (CAP) and protects mice from acute kidney injury (AKI). Direct innervation of the kidney, by afferent and efferent neurons, might have a role in modulating and responding to inflammation in various diseases, either locally or by providing feedback to regions of the central nervous system that are important in the inflammatory reflex pathway. Increased sympathetic drive to the kidney has a role in the pathogenesis of hypertension, and selective modulation of neuroimmune interactions in the kidney could potentially be more effective for lowering blood pressure and treating inflammatory kidney diseases than renal denervation. Use of optogenetic tools for selective stimulation of specific neurons has enabled the identification of neural circuits in the brain that modulate kidney function via activation of the CAP. In this Review we discuss evidence for a role of neural circuits in the control of renal inflammation as well as the therapeutic potential of targeting these circuits in the settings of AKI, kidney fibrosis and hypertension.

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Acknowledgements

The authors' research summarized in this review was supported by the NIH under awards 1R01DK105133, R01 DK062324, U18EB021787 and 1S10RR026799-01.

Author information

Affiliations

  1. Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, PO Box 800133, 1300 Jefferson Park Avenue – West Complex, 5 th floor, Charlottesville, Virginia 22908–0133, USA.

    • Mark D. Okusa
  2. Department of Pharmacology, PO Box 800735, 1304 Jefferson Park Avenue, University of Virginia, Charlottesville, Virginia 22908–0735, USA.

    • Diane L. Rosin
  3. Center for Biomedical Science and Center for Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, 350 Community Drive, Manhasset, New York 11030, USA.

    • Kevin J. Tracey

Authors

  1. Search for Mark D. Okusa in:

  2. Search for Diane L. Rosin in:

  3. Search for Kevin J. Tracey in:

Contributions

All authors researched the data for the article, made substantial contributions to discussion of the content, wrote the article and edited or reviewed the manuscript before submission.

Competing interests

M.D.O. and D.L.R. own equity in Adenosine Therapeutics, LLC. K.J.T. is a consultant for SetPoint Medical, Inc.

Corresponding author

Correspondence to Mark D. Okusa.

Glossary

Vagus nerve

The vagus or 10th cranial nerve is a pair of nerve bundles (right and left) that contains axons of both efferent and afferent neurons. The efferent neurons provide cholinergic input to almost all organs in the periphery and some skeletal muscles. Their cell bodies are located in the medulla oblongata. The cell bodies of afferent neurons are located in the nodose ganglia. These neurons carry the majority of sensory information from visceral organs to the CNS.

Subdiaphragmatic vagotomy

Denervation by surgical transection of both trunks of the vagus nerve either below or caudal to the diaphragm.

Nucleus tractus solitarius

A group of neuronal cell bodies in the brainstem that form an integrative centre for sensory information from the vagus, glossopharyngeal and facial nerves. The nucleus tractus solitarius projects to a wide variety of brain regions, including the hypothalamus, thalamus, and medulla, and participates in circuits that regulate autonomic function.

Coeliac ganglion

A cluster of nerve cells in the abdomen that forms part of the prevertebral sympathetic chain and provides sympathetic innervation to most of the digestive tract. The coeliac ganglion is regulated by the preganglionic neurons in the intermediolateral cell column of the spinal cord.

Bilateral cervical vagotomy

Bilateral cervical vagotomy is a surgical transection of the vagus nerve at the level of the neck on both sides. This procedure prevents the flow of information through the nerve in both directions (afferent and efferent) between its origin in the CNS and its targets in the periphery.

Retrograde tract tracing

A technique for identifying neuronal pathways that exploits constitutive axonal transport to trace the movement of specialized proteins, markers or viruses (which can be visualized by various means) from their point of exogenous introduction in a target field of interest (synaptic terminals) to the cell bodies of those axons (retrograde transport). By contrast, anterograde tracing traces the transport of markers from the cell body region in the direction of the synapse.