ReviewSympathetic innervation of the kidney in health and disease: Emphasis on the role of purinergic cotransmission
Introduction
We start with an anecdote concerning the lack of early attention to the roles of sympathetic nerves in the kidney. GB was present at a lecture by a leading kidney physiologist. During the discussion after the talk, the speaker was asked why he did not consider the influence of nerves on the various mechanisms he had discussed. ‘That is because the nerves in the kidney are not important’, he replied, ‘because the kidney functions perfectly well after denervation’. Clearly an unacceptable response. Influenced by the beautiful early studies of synaptic transmission in skeletal muscle, ganglia and in the CNS, peopled looked, but did not find, specialised neuroeffector synapses (boutons) on smooth muscle and non-excitable cells in the peripheral system. However, it is clear that non-synaptic transmission is characteristic of neuroeffector transmission in the periphery. Innervation involves release of neurotransmitters from autonomic nerve varicosities making transient contact with effector cells, which possess the receptors to mediate junctional transmission (see Burnstock, 2008). This is described in Section 2.
Another major advance was made when cotransmission involving two or more transmitters was recognised (see Burnstock, 1976). This was in conflict with what was known as Dale's Principle that one nerve only released one transmitter, with the belief that sympathetic nerves release noradrenaline (NA) and parasympathetic nerves acetylcholine. In particular it is now well established that sympathetic nerves release adenosine 5′-triphosphate (ATP) and NA as cotransmitters to both visceral and vascular targets, together with neuropeptide Y (NPY), although this usually acts as a prejunctional modulator after release rather than as a cotransmitter (Burnstock, 2007). The evidence for sympathetic cotransmission will be discussed in Section 3.
Sympathetic nerves in the kidney are involved in a number of physiological processes, including control of renal blood flow, glomerular filtration rate, reabsorption of water, sodium and other ions, release of renin and production of prostanoids. These roles will be explored in the following sections. Finally, the roles of sympathetic nerves in pathophysiological conditions, such as hypertension, diabetes and hypoglycaemia will be discussed. Reviews concerned with purinergic signalling and kidney function are available (Bailey et al., 2012, Leipziger, 2016, Praetorius and Leipziger, 2010).
Section snippets
Non-synaptic transmission at sympathetic neuroeffector junctions
Non-synaptic sympathetic nerve transmission to smooth muscle and non-muscular cells has been recognised (see Burnstock, 1986, Burnstock, 2004, Burnstock and Iwayama, 1971, Gabella, 1995). Transmission is ‘en passage’, where transmitter is released from varicosities that come close to effector cells. Sympathetic nerve fibres become varicose in the vicinity of the effector tissue (Fig. 1; Fig. 2a and b). The width of the junctional cleft is variable; prejunctional thickening on varicosities
Sympathetic nerve cotransmission
The concept of purinergic neurotransmission (i.e. ATP as an extracellular signalling molecule) was proposed in 1972 and ATP was claimed to be a non-adrenergic, non-cholinergic (NANC) transmitter in the gut and urinary bladder (Burnstock, 1972). ATP was shown to be released from sympathetic nerves supplying the guinea pig taenia coli as well as from the intrinsic NANC inhibitory nerves (Su et al., 1971). This was suggestive that ATP may be a cotransmitter with NA in sympathetic nerves and,
Sympathetic innervation of kidney: general
It is well established that the kidneys and ureters are innervated by sympathetic, parasympathetic and sensory nerves (Ansell and Gee, 1990, Segura et al., 1996). Anatomically, most of the renal sympathetic innervation derives from prevertebral and paravertebral ganglia including the renal plexus located around the renal artery (Ferguson et al., 1986). The postganglionic sympathetic nerve fibres (axons) from these ganglia project along the renal arteries and intrarenal vascular system, and they
Sympathetic nervous control of glomerular filtration rate
The macula densa cells are the sensing component of the tubuloglomerular feedback (TGF) mechanism and respond to changes in tubular fluid composition by transmitting signals to the afferent arterioles concerned with the regulation of preglomerular vascular resistance and filtered load to the tubules (Nishiyama and Navar, 2002). ATP released from both sympathetic nerves and following paracrine release from macula densa cells, is involved in the mechanism of TGF (Nishiyama and Navar, 2002). Data
Sympathetic nervous control of renin secretion
The renin-secreting juxtaglomerular cells in the kidney are modified vascular smooth muscle cells that are innervated by sympathetic nerves. ATP increases renin release from juxtaglomerular cells (Gaál et al., 1976). Sympathetic junctional cotransmission mediated by NA and ATP releases renin from epithelioid juxtaglomerular cells and vascular smooth muscle cells of the mouse kidney afferent arterioles (Bührle et al., 1986). A contribution of P2Y11 receptor-mediated effects to sympathetic
Sympathetic modulation of resorption of water, sodium and other ions
One function of the sympathetic nerves in the kidney is generally associated with stimulation of renal tubular sodium reabsorption and decreased urinary sodium excretion via α1B adrenoceptors on tubular epithelium (DiBona, 2000, Johns et al., 2011, Kobayashi and Takei, 1996).
There is evidence for the involvement of ATP co-transmission with NA in sympathetic nerves supplying renal collecting ducts, since P2X and P2Y ATP-receptors have been identified on nephron epithelium (Birch et al., 2013,
Hypertension
Hypertension is associated with sympathetic hyperactivity and chronic kidney disease (see Amann and Veelken, 2003). It was suggested that ATP-induced hypotension is associated with attenuation of sympathetic efferent nerve activity mediated through vagal afferent pathways, via reflex activation, and vagal afferent impulses may be one of the mechanisms that inhibit reflex sympathetic activities, such as rebound hypertension after ATP-induced hypotension (Taneyama et al., 1991). The purinergic
Conclusions
In summary, the present review has focused on the roles of sympathetic nerves at different sites in the kidney. Emphasis is placed on the roles played by ATP released as a cotransmitter with NA from sympathetic nerves. Their influence on control of glomerular filtration rate and renin secretion is described. In addition emphasis is made of the neglected role of sympathetic nerves in modulating the transport of water, sodium and other ions in the collecting duct of the nephron. This information
Funding
The authors received no funding for the writing of this review.
Acknowledgements
We would like to thank Dr. Gillian E. Knight for her outstanding editorial assistance.
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