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  • Review Article
  • Published:

Targeting neural reflex circuits in immunity to treat kidney disease

Nature Reviews Nephrology volume 13, pages 669–680 (2017)Cite this article

Subjects

Key Points

  • Neural circuits that control immunity and inflammation provide novel targets for the treatment of kidney disease and hypertension

  • Activation of the cholinergic anti-inflammatory pathway (CAP) blocks splenic-dependent systemic inflammation and acute kidney injury (AKI); non-invasive, nonpharmacological approaches to activate the CAP include ultrasound application and vagus nerve stimulation

  • Neural circuits that directly regulate kidney function or carry sensory feedback from the kidney to the central nervous system could provide additional mechanisms for bidirectional neuroimmunomodulation of kidney disease

  • Interactions between neural circuits and the immune system have important roles in the pathogenesis of hypertension and renal fibrosis

  • Further defining neuroimmunomodulatory pathways in hypertension could enable the development of selective neuronal stimulatory or inhibitory strategies for lowering blood pressure that could potentially be more effective than renal denervation

  • Optogenetic tools provide unprecedented opportunities to dissect the neural pathways that control immunity and inflammation and enable the identification of novel approaches to therapy for kidney diseases

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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Figure 1: The inflammatory reflex.
Figure 2: Neural circuitry of efferent and afferent innervation in the kidney.

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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.

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Authors and 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, 22908–0133, Virginia, USA

    Mark D. Okusa

  2. Department of Pharmacology, PO Box 800735, 1304 Jefferson Park Avenue, University of Virginia, Charlottesville, 22908–0735, Virginia, 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, 11030, New York, USA

    Kevin J. Tracey

Authors
  1. Mark D. Okusa
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  2. Diane L. Rosin
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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.

Corresponding author

Correspondence to Mark D. Okusa.

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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.

PowerPoint slides

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.

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Okusa, M., Rosin, D. & Tracey, K. Targeting neural reflex circuits in immunity to treat kidney disease. Nat Rev Nephrol 13, 669–680 (2017). https://doi.org/10.1038/nrneph.2017.132

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