Chapter 8Renorenal Reflexes

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The identification of a reflex originating in one kidney and affecting contralateral renal function was first demonstrated in the early 1980s. Studies in healthy normotensive rats examining the effects of unilateral renal denervation (efferent plus afferent) on ipsilateral and contralateral renal function found that unilateral renal denervation produced an increase in ipsilateral urinary sodium excretion and a concomitant decrease in contralateral urinary sodium excretion, resulting in unchanged total (ipsilateral + contralateral) urinary sodium excretion. The fall in contralateral urinary sodium excretion was due to an increase in contralateral ERSNA, i.e., a renorenal reflex response [43, 60] (Figure 8.1). These studies suggest that the afferent renal nerves exert a tonic inhibitory effect on ERSNA. Importantly, subsequent studies examining the effects of activation of the afferent renal mechanosensory nerves have confirmed the inhibitory nature of the renorenal reflexes in healthy animals.

FIGURE 8.1. In rats, the increase in ipsilateral urinary sodium excretion (solid lines) produced by unilateral renal denervation is accompanied by a decrease in contralateral urinary sodium excretion, due to an increase in contralateral ERSNA (dashed lines); demonstration of inhibitory natriuretic renorenal reflexes [modified from DiBona and Kopp [58]].

FIGURE 8.1

In rats, the increase in ipsilateral urinary sodium excretion (solid lines) produced by unilateral renal denervation is accompanied by a decrease in contralateral urinary sodium excretion, due to an increase in contralateral ERSNA (dashed lines); demonstration (more...)

8.1. ACTIVATION OF AFFERENT RENAL SENSORY NERVES BY PHYSIOLOGICAL STIMULI

Increases in renal pelvic pressure that stretch the renal pelvic wall tissue results in activation of renal mechanosensory nerves located among smooth muscle cells (Figure 7.1). Mechanical deformation of nerve endings produced by stretch is considered the primary mechanism of mechanoreceptor activation [30]. One of the first studies demonstrating that the afferent renal mechanosensory nerves in the renal pelvic wall were activated by increases in renal pelvic pressure within the physiological range examined the effects of short-term volume expansion on ARNA in cats [85]. This study showed that increasing urine flow rate by short-term volume expansion resulted in parallel increases in renal pelvic pressure and ARNA. Importantly, the activation threshold of the mechanosensory nerves was <5 mmHg above baseline pelvic pressure. Because this renal pelvic pressure is within the range of that commonly seen during high urine flow rate [194, 227], these findings suggested that the renal pelvic mechanosensory nerves are activated by increases in renal pelvic pressure within the physiological range. Measurements of ERSNA and ARNA in the same rat suggested that the increases in ARNA produced by volume expansion contribute to the reduction in ERSNA, which previously has been contributed solely to activation of atrial receptors [177].

To study the mechanisms involved in the activation of the renal sensory nerves in the absence of changes in renal circulation produced by volume expansion, the renal pelvis was stretched by elevation of a fluid-filled ureteral catheter elevated to different levels above the kidney in rats. These experiments showed that graded increases in renal pelvic pressure resulted in graded increases in ARNA with the activation threshold being between 3 and 5 mm Hg [163] (Figure 8.2), i.e., a similar activation threshold as that produced by volume expansion. The increases in ARNA decreased contralateral ERSNA, which in turn increased contralateral urinary sodium excretion [159, 162, 179] (Figure 6.1). Ipsilateral renal denervation blocks the increases in urinary sodium excretion demonstrating that stimulation of afferent renal mechanosensory nerves activates an inhibitory bilateral renorenal reflex mechanism. The afferent renal nerves are not responsive to urinary NaCl concentrations within the physiological range as shown by lack of increases in ARNA in response to renal pelvic perfusion with NaCl at <900 mM.

FIGURE 8.2. In rats fed normal sodium diet, graded increases in renal pelvic pressure result in graded increases in afferent renal nerve activity (ARNA) with an activation threshold of ≤5 mm Hg [modified from Kopp et al.

FIGURE 8.2

In rats fed normal sodium diet, graded increases in renal pelvic pressure result in graded increases in afferent renal nerve activity (ARNA) with an activation threshold of ≤5 mm Hg [modified from Kopp et al. [163]]. Reproduced with permission (more...)

The functional importance of the natriuretic renorenal reflexes in the renal control of total body sodium was supported by the findings that the responsiveness of the renal sensory nerves is modulated by dietary sodium. Studies examining the responsiveness of the afferent renal mechanosensory nerves in rats fed various sodium diets showed that in comparison to dietary low sodium intake, dietary high sodium intake enhances the responsiveness of the afferent renal mechanosensory nerves [144]. At every level of renal pelvic pressure, the increases in both ARNA and urinary sodium excretion are greater during dietary high sodium intake compared with dietary low sodium intake (Figure 8.3). Importantly, in rats fed high sodium diet, the threshold of activation is 2–3 mmHg suggesting that the afferent renal nerves are tonically active in high sodium dietary conditions.

FIGURE 8.3. In rats fed high sodium diet (solid lines), graded increases in renal pelvic pressure result in graded increases in ipsilateral afferent renal nerve activity (ARNA) and contralateral urinary sodium excretion (UNaV) that are of a greater magnitude than those in rats fed low sodium diet (dashed lines).

FIGURE 8.3

In rats fed high sodium diet (solid lines), graded increases in renal pelvic pressure result in graded increases in ipsilateral afferent renal nerve activity (ARNA) and contralateral urinary sodium excretion (UNaV) that are of a greater magnitude than (more...)

8.2. SELECTIVE AFFERENT RENAL DENERVATION–DORSAL RHIZOTOMY

The importance of the renorenal reflex-induced inhibition of ERSNA in the control of body fluid and sodium homeostasis was evaluated by selective bilateral afferent renal denervation produced by dorsal rhizotomy (DRX) at T9–L1. Cutting the dorsal roots from T9 to L1 interrupts the afferent renal neural input to the central nervous system [65]. Both DRX and sham-DRX rats were able to establish external sodium balance on a normal and high sodium dietary intake. However, the process of achieving external sodium balance while consuming an increased dietary sodium intake resulted in significantly higher mean arterial pressure in DRX rats than in sham-DRX rats [142, 158] (Figure 8.4). Arterial pressure was similar in rats fed normal sodium diet [142, 158]. Thus, the afferent renal nerves are essential for achieving sodium balance during increased dietary sodium intake. Rats lacking intact afferent renal innervation can only achieve sodium balance at the cost of increased mean arterial pressure. These findings are supported by the afferent renal nerves being tonically activated in high sodium dietary conditions [144]. Thence, afferent renal denervation leads to salt-sensitive hypertension. Among the mechanisms contributing to the development of salt-sensitive hypertension in the DRX rats are increased ERSNA and increased responsiveness of ERSNA to various sympathetic stimuli due, at least in part, to impairment of the arterial baroreflex function [158].

FIGURE 8.4. Mean arterial pressure was measured over a period of 1 week in conscious rats fed either high or normal sodium diet for 3 weeks following dorsal rhizotomy from T9 to L1 to interrupt afferent renal neural input to the central nervous system or sham operation.

FIGURE 8.4

Mean arterial pressure was measured over a period of 1 week in conscious rats fed either high or normal sodium diet for 3 weeks following dorsal rhizotomy from T9 to L1 to interrupt afferent renal neural input to the central nervous system or sham operation. (more...)

In view of these studies, it is interesting to note that rats, neonatally treated with capsaicin to destroy the sensory innervation of all organs, develop salt-sensitive hypertension [244]. The salt-sensitive hypertension in DRX rats [142, 158] would suggest that the lack of intact afferent renal innervation in the capsaicin-treated rats may contribute to the increased arterial pressure observed in these rats when fed high sodium diet.

8.3. INTERACTION BETWEEN EFFERENT AND AFFERENT RENAL NERVE ACTIVITY

Not only is the renal pelvic wall innervated by afferent sensory nerves, but it is also innervated by efferent sympathetic nerves [149]. Many of the sympathetic nerve fibers are in close contact with the sensory nerves. Confocal microscopy with a higher resolution revealed that the sympathetic nerves and the sensory nerves are separate fibers that often are intertwined [149] (Figure 8.5). These studies provide anatomical support for a functional interaction between the efferent and afferent renal nerves. Indeed, as discussed above, in normotensive rats, activation of the afferent renal sensory nerves leads to decreases in ERSNA and natriuresis, an inhibitory renorenal reflex response [159]. However, not only do increases in ARNA decrease ERSNA, but increases in ERSNA also increase ARNA [145, 149, 150, 157] (Figure 8.6). The increased ARNA will, in turn, decrease ERSNA via activation of the renorenal reflexes, a negative feedback mechanism, to maintain low-level ERSNA (Figure 8.7).

FIGURE 8.5. The sympathetic nerves located in the renal pelvic wall (a) are in close contact with the sensory nerves (b) as shown by the color yellow (c) (arrows).

FIGURE 8.5

The sympathetic nerves located in the renal pelvic wall (a) are in close contact with the sensory nerves (b) as shown by the color yellow (c) (arrows). Confocal microscopy at a higher resolution showed the sympathetic and sensory nerves to be separate (more...)

FIGURE 8.6. In anesthetized rats, thermal cutaneous stimulation produced by placing the rat's tail in warm water results in a general activation of the sympathetic nervous system as shown by large increases in mean arterial pressure (MAP) and ERSNA.

FIGURE 8.6

In anesthetized rats, thermal cutaneous stimulation produced by placing the rat's tail in warm water results in a general activation of the sympathetic nervous system as shown by large increases in mean arterial pressure (MAP) and ERSNA. The increase (more...)

FIGURE 8.7. There is a reciprocal interaction between ERSNA and ARNA in which increases in ERSNA increase ARNA, which in turn will decrease ERSNA via activation of the renorenal reflexes, a negative feedback mechanism, to maintain low-level ERSNA.

FIGURE 8.7

There is a reciprocal interaction between ERSNA and ARNA in which increases in ERSNA increase ARNA, which in turn will decrease ERSNA via activation of the renorenal reflexes, a negative feedback mechanism, to maintain low-level ERSNA.

Changes in ERSNA modulate ARNA by the release of the neurotransmitter norepinephrine. The increases in ARNA produced by reflex increases in ERSNA are reduced by renal pelvic administration of prazosin, an α1-adrenoceptor antagonist, and enhanced by rauwolscine, an α2-adrenoceptor antagonist [149] (Figure 8.8). It is unlikely that the interaction between ERSNA and ARNA is related to increased pelvic contractile responses induced by neurally released norepinephrine. Whereas, ARNA is increased by norepinephrine concentrations in the pmolar range, μmolar concentrations of norepinephrine are required to modulate/increase pelvic contractility [92]. Similar to the responsiveness of the renal mechanosensory nerves being modulated by dietary sodium, the interaction between ERSNA and ARNA is also modulated by dietary sodium. Reflex increases in ERSNA result in much larger increases in ARNA in rats fed high sodium diet than in rats fed low sodium diet (Figure 8.9) underlining the physiological importance of the ERSNA-induced increases in ARNA [150, 157]. Examining the mechanisms involved in the reduced responsiveness of the renal sensory nerves to increases in ERSNA in rats fed low sodium diet, it became clear that renal pelvic administration of losartan alone failed to enhance the ERSNA-induced increase in ARNA or the norepinephrine-induced increase in substance P. These findings suggested that the impaired responsiveness of the renal sensory nerves to norepinephrine involves additional mechanisms upstream of PGE2, most likely increased activation of α2-adrenoceptors exerting suppression of PGE2 release. This hypothesis was confirmed in subsequent studies, which showed that a combination of losartan plus rauwolscine enhanced the responsiveness of the renal sensory nerves to norepinephrine toward that seen in high sodium diet rats [150]. Taken together, these results suggest that in high sodium diet, the enhanced ARNA response to increases in ERSNA and/or increases in renal pelvic pressure would lead to enhanced inhibitory renorenal reflex control of ERSNA to minimize sodium retention. Conversely, in low sodium diet, the suppressed ARNA responses to increases in ERSNA and/or increases in renal pelvic pressure would result in little or no inhibition of ERSNA, which eventually would lead to sodium retention (Figure 8.10).

FIGURE 8.8. Reflex increases in ERSNA produced by thermal cutaneous stimulation (tail in warm water) result in increases in ARNA that are reduced by renal pelvic perfusion with the α1-adrenoceptor antagonist prazosin (A) and enhanced by the α2-adrenoceptor antagonist rauwolscine (B).

FIGURE 8.8

Reflex increases in ERSNA produced by thermal cutaneous stimulation (tail in warm water) result in increases in ARNA that are reduced by renal pelvic perfusion with the α1-adrenoceptor antagonist prazosin (A) and enhanced by the α2-adrenoceptor (more...)

FIGURE 8.9. Reflex increases in ERSNA result in much greater increases in ARNA in rats fed high sodium diet than in rats fed low sodium diet.

FIGURE 8.9

Reflex increases in ERSNA result in much greater increases in ARNA in rats fed high sodium diet than in rats fed low sodium diet.

FIGURE 8.10. Increased activation of α2-adrenoceptors on renal pelvic sensory nerves, together with increased endogenous renal ANG II, contributes to the reduced responsiveness of the renal sensory nerves to norepinephrine in low-sodium dietary conditions (left).

FIGURE 8.10

Increased activation of α2-adrenoceptors on renal pelvic sensory nerves, together with increased endogenous renal ANG II, contributes to the reduced responsiveness of the renal sensory nerves to norepinephrine in low-sodium dietary conditions (more...)

Thus, the dietary modulation of the ERSNA-induced increases in ARNA contributes to the maintenance of volume and sodium homeostasis during various dietary sodium intakes.