Efferent Renal Nerve Activity Research Articles

Afferent renal innervation in anti-Thy1.1 nephritis in rats

Afferent renal nerves exhibit a dual function controlling central sympathetic outflow via afferent electrical activity and influencing intrarenal immunological processes by releasing peptides such as calcitonin gene-related peptide (CGRP). We tested the hypothesis that increased afferent and efferent renal nerve activity occur with augmented release of CGRP in anti-Thy1.1 nephritis, in which enhanced CGRP release exacerbates inflammation. Nephritis was induced in Sprague-Dawley rats by intravenous injection of OX-7 antibody (1.75 mg/kg), and animals were investigated neurophysiologically, electrophysiologically, and pathomorphologically 6 days later. Nephritic rats exhibited proteinuria (169.3 ± 10.2 mg/24 h) with increased efferent renal nerve activity (14.7 ± 0.9 bursts/s vs. control 11.5 ± 0.9 bursts/s, n = 11, P < 0.05). However, afferent renal nerve activity (in spikes/s) decreased in nephritis (8.0 ± 1.8 Hz vs. control 27.4 ± 4.1 Hz, n = 11, P < 0.05). In patch-clamp recordings, neurons with renal afferents from nephritic rats showed a lower frequency of high activity following electrical stimulation (43.4% vs. 66.4% in controls, P < 0.05). In vitro assays showed that renal tissue from nephritic rats exhibited increased CGRP release via spontaneous (14 ± 3 pg/mL vs. 6.8 ± 2.8 pg/ml in controls, n = 7, P < 0.05) and stimulated mechanisms. In nephritic animals, marked infiltration of macrophages in the interstitium (26 ± 4 cells/mm2) and glomeruli (3.7 ± 0.6 cells/glomerular cross-section) occurred. Pretreatment with the CGRP receptor antagonist CGRP8-37 reduced proteinuria, infiltration, and proliferation. In nephritic rats, it can be speculated that afferent renal nerves lose their ability to properly control efferent sympathetic nerve activity while influencing renal inflammation through increased CGRP release.

Does glucagon-like peptide-1 induce diuresis and natriuresis by modulating afferent renal nerve activity?

Glucagon-like peptide-1 (GLP-1), an incretin hormone, has diuretic and natriuretic effects. The present study was designed to explore the possible underlying mechanisms for the diuretic and natriuretic effects of GLP-1 via renal nerves in rats. Immunohistochemistry revealed that GLP-1 receptors were avidly expressed in the pelvic wall, the wall being adjacent to afferent renal nerves immunoreactive to calcitonin gene-related peptide, which is the dominant neurotransmitter for renal afferents. GLP-1 (3 μM) infused into the left renal pelvis increased ipsilateral afferent renal nerve activity (110.0 ± 15.6% of basal value). Intravenous infusion of GLP-1 (1 µg·kg-1·min-1) for 30 min increased renal sympathetic nerve activity (RSNA). After the distal end of the renal nerve was cut to eliminate the afferent signal, the increase in efferent renal nerve activity during intravenous infusion of GLP-1 was diminished compared with the increase in total RSNA (17.0 ± 9.0% vs. 68.1 ± 20.0% of the basal value). Diuretic and natriuretic responses to intravenous infusion of GLP-1 were enhanced by total renal denervation (T-RDN) with acute surgical cutting of the renal nerves. Selective afferent renal nerve denervation (A-RDN) was performed by bilateral perivascular application of capsaicin on the renal nerves. Similar to T-RDN, A-RDN enhanced diuretic and natriuretic responses to GLP-1. Urine flow and Na+ excretion responses to GLP-1 were not significantly different between T-RDN and A-RDN groups. These results indicate that the diuretic and natriuretic effects of GLP-1 are partly governed via activation of afferent renal nerves by GLP-1 acting on sensory nerve fibers within the pelvis of the kidney.

Renal Nerves and Long-Term Control of Arterial Pressure.

The objective of this review is to provide an in-depth evaluation of how renal nerves regulate renal and cardiovascular function with a focus on long-term control of arterial pressure. We begin by reviewing the anatomy of renal nerves and then briefly discuss how the activity of renal nerves affects renal function. Current methods for measurement and quantification of efferent renal-nerve activity (ERNA) in animals and humans are discussed. Acute regulation of ERNA by classical neural reflexes as well and hormonal inputs to the brain is reviewed. The role of renal nerves in long-term control of arterial pressure in normotensive and hypertensive animals (and humans) is then reviewed with a focus on studies utilizing continuous long-term monitoring of arterial pressure. This includes a review of the effect of renal-nerve ablation on long-term control of arterial pressure in experimental animals as well as humans with drug-resistant hypertension. The extent to which changes in arterial pressure are due to ablation of renal afferent or efferent nerves are reviewed. We conclude by discussing the importance of renal nerves, relative to sympathetic activity to other vascular beds, in long-term control of arterial pressure and hypertension and propose directions for future research in this field. © 2017 American Physiological Society. Compr Physiol 7:263-320, 2017.

Targeting the Sympathetic Nervous System

Evidence has accumulated during the past several decades, strongly suggesting that abnormalities of the sympathetic nervous system contribute to the development and maintenance of multiple disease states, including hypertension, heart failure, diabetes mellitus, sleep apnea, kidney disease, and atrial fibrillation.1 The renal nerves have been identified as important contributors to the development of hypertension in both experimental animals and humans.2 Patients with essential hypertension and other disease states often have increased efferent sympathetic drive to the kidneys as demonstrated by elevated rates of renal norepinephrine spillover.1,2 In addition to increased renal efferent nerve activity, there is indirect evidence for increased renal afferent activity in patients with essential hypertension.3 Nonselective surgical sympathectomy has been effectively used as a treatment for severe hypertension,4 with a remarkable difference in outcomes at 5 years of follow-up. Recently developed endovascular catheter technology has allowed selective denervation of the human kidney using radiofrequency (RF) energy delivered via the renal artery lumen.5 Although the initial clinical trials with this minimally invasive technique have documented the safety and efficacy of such an approach, critical questions have been raised pertaining to long-term safety, mechanisms of action, appropriate patient selection, reductions in ambulatory blood pressure (BP), definition and level of responder rates, need for identification of characteristics that predict nonresponse, phenomenon of a delayed response, and several others.6 Here, we address several of these key questions. Catheter-based renal nerve ablation interrupts both efferent and afferent nerves (Figure 1). It is well established that activation of renal sympathetic efferents can decrease renal blood flow, increase tubular sodium and water reabsorption, and increase renin release.2 However, there is emerging evidence that renal afferent signaling may be as important as renal efferent activity in elevating BP. Activation of renal afferents can cause a …

Abstract 537: Segment-specific Intrathecal Injection of Metformin Protects Against High Fat Diet-induced Impairment in Afferent Renal Nerves and Renal Function

Metformin (Met), a drug for treating type 2 diabetes by suppressing glucose production and increasing insulin sensitivity, may possess neuroprotective and neurogenesis effects. We test the hypotheses 1) that high fat diet (HFD) intake impairs afferent renal nerves expressing transient receptor potential vanilloid 1 (TRPV1) channels, leading to increased efferent renal nerve activity (ERNA), decreased renal function, and hypertension; and 2) that Met given intrathecally (i.t.) to segments (T8-L3) supplying the kidney prevents HFD-induced impairment in afferent renal nerves, renal function, and hypertension. Met (1 ng/kg, i.t. daily) or vehicle was given to rats fed a HFD or normal fat diet (Con) for 8 weeks. Glucose or insulin tolerance was impaired to the same degree between rats fed HFD with and without Met treatment. HFD decreased renal TRPV1 expression, plasma levels of calcitonin gene-related peptide, and afferent renal nerve activity (ARNA, Con: 126±11, Met: 136±14, HFD: 77±7, HFD+Met: 121±8, p&lt;0.05) in response to intra-pelvis perfusion of capsaicin (a TRPV1 agonist at 4 mM, 3 min, 20 ml/min), which were prevented by Met. HFD increased renal tyrosine hydroxylase contents, ERNA responses to intrathecal injection of muscimol (a GABA-A receptor agonist at 3 nmol/kg), and urinary norepinephrine levels, which were prevented by Met. HFD decreased creatinine clearance (Con: 0.40±0.04, Met: 0.52±0.07, HFD: 0.12±0.05, HFD+Met: 0.30±0.04 ml/min/100 gbwt, p&lt;0.05) and urinary Na+ excretion, and increased levels of urinary albumin, plasma urea, renal collagen deposition, renal connective tissue growth factor, and systolic blood pressure (Con: 132±1, Met: 130±1, HFD: 145±3, HFD+Met: 132±1 mmHg, p&lt;0.05), which were prevented or attenuated by Met. Thus, HFD impairs TRPV1-positive afferent renal nerves and renal function, and increases renal sympathetic nerve activity and blood pressure. Segment-specific intrathecal injection of Met protects against HFD-induced impairment in afferent renal nerves and renal function, and prevents HFD-induced hypertension.

Abstract 536: Resiniferatoxin-induced Disorders in Glucose Homeostasis and Hypertension: Role of Trpv1-positive Sensory Nerves

Resiniferatoxin (RTX), an ultrapotent agonist of the transient receptor potential vanilloid 1 (TRPV1) channels, has been used to relieve pain in humans in clinical trials that are ongoing, completed, or terminated due to its unwanted side effects that have not been well understood. We test the hypothesis that RTX causes disorders in glucose homeostasis, renal functional and structural impairment, and hypertension via insulin receptor-mediated increases in sympathetic nerve activity. Male Wistar rats were injected with RTX (0.2 mg/kg, i.p.) or vehicle. Pancreatic and renal TRPV1 levels were decreased 4 weeks after RTX treatment, confirming effective and lasting treatment of RTX (p&lt;0.05). RTX decreased plasma insulin levels (Control: 1.4±0.1 vs RTX: 0.8±0.1 ng/ml, p&lt;0.05) but improved glucose tolerance (p&lt;0.05). RTX increased the translocation of skeletal muscle glucose transporter 4 (Glut4) from cytosol to cell membrane indicated by increased membrane fraction but decreased cytosol fraction of Glut4 in RTX-treated rats (p&lt;0.05). RTX increased levels of phosphorylated insulin receptor substrate 1 in sympathetic ganglia (Control: 0.43±0.04 vs RTX: 0.65±0.08, p&lt;0.05), renal tyrosine hydroxylase contents, and urinary norepinephrine concentrations (Control: 352±70 vs RTX: 781±142 ng/day, p&lt;0.05). When TRPV1 expressed in sensory neurons and their nerve endings innervating the kidney was knocked down by intrathecal (i.t) injection of TRPV1 shRNA, insulin (3nmol/kg, i.t.)-induced increases in efferent renal nerve activity were further enhanced (Control: 40±3 vs TRPV1 shRNA: 53±2, p&lt;0.05). RTX decreased creatinine clearance (Control: 0.58±0.04 vs RTX: 0.46±0.04 ml/min/100 gbwt, p&lt;0.05) and increased levels of plasma urea, urinary albumin, renal connective tissue growth factor, and systolic blood pressure (Control: 128±1 vs RTX: 143±2 mmHg, p&lt;0.05). Thus, RTX treatment causes disorders in glucose homeostasis, renal functional and structural impairment, and hypertension, possibly via increasing sympathetic nerve activity resulting from enhanced stimulatory effects of the insulin receptors expressed in sympathetic nerves and weakened inhibitory effects of TRPV1-positive sensory nerves on sympathetic nerves.

Abstract 8938: Heightened Renal Sympathetic Nerve Activity in Response to High Salt Intake After Renal Ischemia-Reperfusion Injury: Role Of TRPV1

Increased salt sensitivity occurs following ischemia-reperfusion (I/R) injury of the kidney. We test the hypothesis that renal sympathetic nerve activity is increased in response to high salt (HS) intake after I/R of the kidney, which can be prevented by activation of the transient receptor potential vanilloid type 1 (TRPV1) prior to renal I/R. Rats were fed a 0.4 % NaCl diet for 5 wks after I/R, following by a 4 % NaCl diet for 4 more wks in four groups: Sham, I/R, I/R+high dose capsaicin (HDC), and I/R+low dose capsaicin (LDC). TRPV1 was activated or down-regulated by s.c. injection of a low (1 mg/kg) or high (100 mg/kg) dose of capsaicin, respectively, 3 hrs before I/R. Renal TRPV1 protein expression was decreased after I/R and further reduced in I/R+HDC but unchanged in I/R+LDC compared to Sham (Sham: 0.44±0.04 vs I/R: 0.26±0.02 vs I/R+HDC: 0.17±0.01 vs I/R+LDC: 0.38±0.05, p&lt;0.05). Systolic blood pressure and renal excretory function were not different among four groups 5 wks after I/R, but gradually elevated or deteriorated, respectively, when switched to HS for the remaining 4 wks in I/R and I/R+HDC but not I/R+LDC, with greater intensity in I/R+HDC ( p&lt;0.05). At the end of HS treatment, afferent renal nerve activity in response to unilateral intra-pelvis administration of capsaicin was decreased in I/R and further suppressed in I/R+HDC but unchanged in I/R+LDC (Sham: 123±7 vs I/R: 81±9 vs I/R+HDC: 37±6 vs I/R+LDC: 120±13%, p&lt;0.05). Efferent renal nerve activity in response to intrathecal administration of muscimol (3 nmol/kg), a selective activator of GABA-A receptors, was decreased in I/R and further suppressed in I/R+HDC but unchanged in I/R+LDC (Sham: -21±1 vs I/R: -42±3 vs I/R+HDC: -53±2 vs I/R+LDC: -25±4%, p&lt;0.05). Urinary norepinephrine levels were increased in I/R and further elevated in I/R+HDC but unchanged in I/R+LDC (Sham: 785±98 vs I/R: 1311±98 vs I/R+HDC: 1731±140 vs I/R+LDC: 1018±85 ng/day, p&lt;0.05). These data show that renal sympathetic drive is increased in response to HS intake after I/R, which can be prevented by TRPV1 activation prior to renal I/R, indicating that TRPV1 may prevent increased salt sensitivity after I/R via suppression of heightened renal sympathetic nerve activity.

Ioxitalamate Induces Renal Tubular Apoptosis via Activation of Renal Efferent Nerve–Mediated Adrenergic Signaling, Renin Activity, and Reactive Oxygen Species Production in Rats

To investigate the unrecognized role of renal efferent nerve activity (RENA) in iodinated contrast media (CM)-induced acute kidney injury, we explored the effects of CM on RENA, renal hemodynamics, plasma renin activity (PRA), reactive oxygen species (ROS) production, and renal injury in rats. Four types of CM including ioxitalamate (high osmolar and ionic), ioxaglate (low osmolar and ionic), iohexol (low osmolar and nonionic), and iodixanol (iso-osmolar and nonionic) were given iv (1600 mg I/kg body weight) to urethane-anesthetized female Wistar rats. We measured RENA by electrophysiologic recording techniques, renal blood flow with Doppler ultrasound, PRA by radioimmunoassay, and ROS by an in vivo chemiluminescence method. We graded the severity of CM-induced vacuoles in cortical tubular cells stained by hematoxylin and eosin and apoptosis production in outer medulla by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. Besides, the effects of pretreatment with iv beta-adrenoceptor antagonist propranolol (10 mg/kg body weight), antioxidant N-acetylcysteine (100 mg/kg body weight), and renal denervation on CM-induced pathophysiologic parameters were determined. Ioxitalamate significantly increased RENA and renal vascular resistance, PRA, renal ROS production within 1 h, and formation of vacuoles and TUNEL apoptosis in renal tubular cells 2 h later; other CM had less effect on these parameters. On the other hand, propranolol, N-acetylcysteine, or renal denervation partially attenuated the ioxitalamate-aggravated responses on RENA, PRA, ROS production, and vacuole and TUNEL apoptosis formation in renal tubular cells. In conclusion, we suggest that ioxitalamate may induce acute tubular injury via aggravation of RENA, adrenergic signaling, PRA, and ROS production.

Protection of Ischemic Preconditioning on Renal Neural Function in Rats with Acute Renal Failure

We tested whether tolerance induced by ischemic preconditioning (IPC) in kidneys was related to renal nerves. Experimental acute renal failure (ARF) in a rat model was induced for 45 min of left renal arterial occlusion (RAO), followed by 6 or 24 h of reperfusion (ischemic reperfusion (I/R) group). The episode of IPC was four cycles of 4 min of RAO at 11 min intervals and then the I/R injury was treated as above (IPC-I/R group). After 6 h of reperfusion, polyuria was found in the I/R group associated with an enhancement of afferent renal nerve activity (ARNA) and a reflexive decrease in efferent renal nerve activity (ERNA). Changes in nerve responses were related with a reduction in neutral endopeptidase (NEP) activity and an increased release of substance P (SP). After 24 h of reperfusion, the I/R group showed oliguria which was associated with a lower ARNA, hyperactivity of ERNA and a nine-fold increase in SP release due to a further 52% loss in NEP activity. Prior IPC treatment did not affect the changed ischemia-induced excretory and nervous activity patterns during the first 6 h of reperfusion, but normalized both responses in the kidneys 24 h after ischemia. The IPC-mediated protection in oliguric ARF was related to the preservation of NEP activity to only 25% loss that caused an increase of SP amounts of only three-fold and a minor change in neurokinin 1 receptor (NK-1R) activities. Finally, both excretory and sensory responses in oliguric ARF after saline loading were significantly ameliorated by IPC. We conclude that IPC results in preservation of the renal sensory response in postischemic kidneys and has a beneficial effect on controlling efferent renal sympathetic nerve activity and excretion of solutes and water.

Impaired responsiveness of renal sensory nerves in streptozotocin-treated rats and obese Zucker diabetic fatty rats: role of angiotensin

Increasing afferent renal nerve activity decreases efferent renal nerve activity and increases urinary sodium excretion. Activation of renal pelvic mechanosensory nerves is impaired in streptozotocin (STZ)-treated rats (model of type 1 diabetes). Decreased activation of renal sensory nerves would lead to increased efferent renal nerve activity, sodium retention, and hypertension. We examined whether the reduced activation of renal sensory nerves in STZ rats was due to increased renal angiotensin activity and whether activation of the renal sensory nerves was impaired in obese Zucker diabetic fatty (ZDF) rats (model of type 2 diabetes). In an isolated renal pelvic wall preparation from rats treated with STZ for 2 wk, PGE2 failed to increase the release of substance P, from 5 +/- 1 to 6 +/- 1 pg/min. In pelvises from sham STZ rats, PGE2 increased substance P release from 6 +/- 1 to 13 +/- 2 pg/min. Adding losartan to the incubation bath increased PGE2-mediated release of substance P in STZ rats, from 5 +/- 1 to 10 +/- 2 pg/min, but had no effect in sham STZ rats. In pelvises from obese ZDF rats (22-46 wk old), PGE2 increased substance P release from 12.0 +/- 1.2 to 18.3 +/- 1.2 pg/min, which was less than that from lean ZDF rats (10.3 +/- 1.6 to 22.5 +/- 2.4 pg/min). Losartan had no effect on the PGE2-mediated substance P release in obese or lean ZDF rats. We conclude that the mechanisms involved in the decreased responsiveness of the renal sensory nerves in STZ rats involve activation of the renin angiotensin system in STZ but not in obese ZDF rats.

Effect of mesenteric vascular congestion on reflex control of renal blood flow

Portal hypertension initiates a splenorenal reflex, whereby increases in splenic afferent nerve activity and renal sympathetic nerve activity cause a decrease in renal blood flow (RBF). We postulated that mesenteric vascular congestion similarly compromises renal function through an intestinal-renal reflex. The portal vein was partially occluded in anesthetized rats, either rostral or caudal to the junction with the splenic vein. Portal venous pressure increased (6.5 +/- 0.1 to 13.2 +/- 0.1 mmHg; n = 78) and mesenteric venous outflow was equally obstructed in both cases. However, only rostral occlusion increased splenic venous pressure. Rostral occlusion caused a fall in RBF (-1.2 +/- 0.2 ml/min; n = 9) that was attenuated by renal denervation (-0.5 +/- 0.1 ml/min; n = 6), splenic denervation (-0.2 +/- 0.1 ml/min; n = 11), celiac ganglionectomy (-0.3 +/- 0.1 ml/min; n = 9), and splenectomy (-0.5 +/- 0.1 ml/min; n = 6). Caudal occlusion induced a significantly smaller fall in RBF (-0.5 +/- 0.1 ml/min; n = 9), which was not influenced by renal denervation (-0.2 +/- 0.2 ml/min; n = 6), splenic denervation (-0.1 +/- 0.1 ml/min; n = 7), celiac ganglionectomy (-0.1 +/- 0.3 ml/min; n = 8), or splenectomy (-0.3 +/- 0.1 ml/min; n = 7). Renal arterial conductance fell only in intact animals subjected to rostral occlusion (-0.007 +/- 0.002 ml.min(-1).mmHg(-1)). This was accompanied by increases in splenic afferent nerve activity (15.0 +/- 3.5 to 32.6 +/- 6.2 spikes/s; n = 7) and renal efferent nerve activity (32.7 +/- 5.2 to 39.3 +/- 6.0 spikes/s; n = 10). In animals subjected to caudal occlusion, there were no such changes in renal arterial conductance or splenic afferent/renal sympathetic nerve activity. We conclude that the portal hypertension-induced fall in RBF is initiated by increased splenic, but not mesenteric, venous pressure, i.e., we did not find evidence for intestinal-renal reflex control of the kidneys.

Elevated mesenteric vascular pressure does not activate the splenorenal reflex in portal hypertension

Portal hypertension increases splenic venous outflow pressure, and triggers a splenorenal reflex reduction in renal blood flow (RBF). Previous studies suggest that mesenteric vascular outflow pressure, which rises in portal hypertension, may also influence renal function. We investigated the role of the intestine in modulating RBF. We reasoned that whereas occlusion of the portal vein rostral to the porto-splenic junction would raise both mesenteric and intrasplenic pressure, thus initiating the splenorenal reflex and reducing RBF, occlusion caudal to the porto-splenic junction would increase only mesenteric venous outflow pressure. Any change in renal sympathetic nerve activity could then be attributed to an intestinal/renal reflex arc. We measured splenic afferent and renal efferent nerve activity during portal vein occlusion. There was no difference in the rise in portal venous pressure when the portal vein was partially occluded rostral or caudal to the porto-splenic junction (6.5 ± 0.2 to 14.6 ± 0.4 mmHg, n= 23). However, whereas rostral occlusion caused an increase in both splenic afferent (9.5 ± 2.1 to 14.7 ± 2.2 spikes/ sec, n=7) and renal efferent (9.1 ± 1.5 to 13.9 ± 3.0 spikes/sec, n=5) nerve activity, there were no such changes during caudal occlusion (Splenic Afferent: 9.3 ± 0.9 to 7.3 ± 1.5 spikes/sec, n= 6; Renal Efferent: 8.2 ± 2.2 to 5.0 ± 1.1 spikes/sec, n=5). In conclusion, the selective increase in mesenteric venous outflow pressure did not alter renal sympathetic nerve activity. We therefore found no evidence for intestinal-renal reflex control of renal function during portal hypertension (HSFC, CIHR).

The effect of an intestinal ischemia-reperfusion injury on renal nerve activity among rats.

An intestinal ischemia-reperfusion injury (IIR) may induce renal tubular dysfunction and a reduction in renal blood flow that may be related to the alteration of renal-nerve activity. A rat model of IIR injury was established. The superior mesenteric artery was clamped for 120 min, constituting the ischemic period, and was then released for 60 min, thus constituting the reperfusion period. Renal-nerve activity, renal function, and hemodynamic changes were recorded during the different periods. The levels of calcitonin gene-related peptide (CGRP) in portal-vein blood and intestinal tissue were investigated here. In the reperfusion period, the efferent renal-nerve activity (ERNA) was markedly elevated (94.3% +/- 21.6% higher than the baseline value), such an elevation being only partially reversed by fluid expansion (29.3% +/- 5.2% higher than the baseline value). The elevation of ERNA contributed to the renal blood-flow reduction from 6.8 +/- 0.3 mL/min/g to 2.0 +/- 0.4 mL/min/g, and decreased diuretic and natriuretic responses. The afferent renal nerve activity (ARNA) was markedly depressed (45.7% +/- 8.1% lower than the baseline value) during the reperfusion period. This depression was not reversed by fluid expansion, suggesting that the baroreflex was not responsible for this effect. The blunted ARNA also contributed to the elevation of ERNA by way of a renorenal reflex. The potent vasodilator neuropeptide in the gut, CGRP, revealed an increased level in the portal-vein blood (92.2 +/- 4.4 pg/mL vs. 57.8 +/- 0.6 pg/mL) and also in intestinal tissue (655.8 +/- 115.9 pg/mL vs. 60.5 +/- 9.4 pg/mL) with a time-matched related pattern with the change to renal-nerve activity, suggesting CGRP's role regarding changes in renal-nerve activity. This study indicates that the elevated ERNA level associated with IIR injury is related to a systemic hypotension-induced baroreflex, the contra-lateral inhibition of ARNA, and possibly also gut-released CGRP. In regards to an IIR injury, the depressed ARNA reflects the involvement of a renal sensory- impairment mechanism.

Pericardial effusion leading to acute renal failure: Two case reports and discussion of pathophysiology

We describe two patients who developed acute renal failure secondary to severe pericardial effusion. In one patient, the pericardial effusion was due to coxsackievirus infection, and in the other patient, it was due to lung cancer. One patient was in cardiac tamponade, and the other was not yet in tamponade, as per echocardiographic criteria. Kidney function was relatively normal in both patients before the pericarditis episodes. In both patients, pericardiocentesis caused immediate massive diuresis with quick recovery of renal function back to baseline. In the first patient, blood urea nitrogen and serum creatinine decreased from 82 mg/dL and 7.6 mg/dL to 71 mg/dL and 4.6 mg/dL in the next 48 hours, then to 23 mg/dL and 1.3 mg/dL 5 days after the pericardiocentesis. In the second patient, blood urea nitrogen and serum creatinine decreased from 109 mg/dL and 2.9 mg/dL to 40 mg/dL and 0.9 mg/dL in the next 48 hours and 17 mg/dL and 0.7 mg/dL 3 days after release of tamponade. Pericardial effusion can affect renal hemodynamics in many different ways, including increased atrial natriuretic peptide secretion, increased renal efferent nerve activity, and increased secretion of renin and vasopressin. Although pericardial effusion is a complication of uremia, acute renal failure per se can occur in nonuremic cases of pericardial effusion. Two cases of acute renal failure resulting from pericardial effusion were reported in the literature in the past. Pericardial effusion should be included in the broad list of prerenal causes of acute renal failure. © 2002 by the National Kidney Foundation, Inc.

Impaired Renal Sensory Responses after Renal Ischemia in the Rat

Renal sensory responses and reflex function were examined in rats 24 h after 45 min of ischemic injury caused by unilateral renal arterial occlusion (RAO). The integrity of renal pelvic mechanoreceptor (MRu)-mediated renorenal reflex was examined. An increase in ipsilateral afferent renal nerve activity (ARNA) and a reflex decrease in efferent renal nerve activity (ERNA) and contralateral diuresis and natriuresis produced by increasing the intrapelvic pressure were seen in sham-operated (Sham) rats, but it was largely attenuated in RAO rats. Using single-fiber recordings of the renal MRu discharge, graded increases in intrapelvic pressure or renal pelvic administration of substance P (SP) resulted in pressure- or concentration-dependent increases in ARNA in the control kidney of Sham rats, whereas attenuated responses were seen in the postischemic kidney of RAO rats. The unresponsiveness of renal MRus in RAO rats was accompanied by an insufficient release of SP. However, the baseline SP release is higher in RAO kidneys due to a reduced neutral endopeptidase (NEP) activity in the renal pelvis of the postischemic kidney. No changes in NK-1 receptor mRNA levels were demonstrated; however, the expression of NK-1 receptors in the plasma membrane of RAO pelvis were decreased, possibly resulting from the internalization of the receptors associated with beta-arrestin trafficking. Renal excretory responses after saline loading were significantly lower in the postischemic kidney of RAO rats than in Sham rats. Responses of ARNA and ERNA were also lower. It is concluded that the defective activation of renal sensory mechanoreceptors in the postischemic kidney results from an inadequate release of SP after mechanostimulation and the reduced functional NK-1 receptors.

Impaired renal sensory responses after unilateral ureteral obstruction in the rat.

Renal responses to the activation of renal sensory receptors were examined in rats after release of 24-h unilateral ureteral obstruction of the left kidney. The integrity of the renorenal reflex was examined in both 24-h unilateral ureteral obstruction-treated (UUO) and sham-operated (Sham) rats. Increased ipsilateral afferent renal nerve activity (ARNA) and reflexly decreased efferent renal nerve activity (ERNA) and increased contralateral diuresis and natriuresis produced by increasing the left intrapelvic pressure were observed in Sham rats but not in UUO rats. The lack of responsiveness of the renorenal reflex in UUO rats was associated with lower release of substance P (SP) and increased neutral endopeptidase (NEP) activity in the renal pelvis in the postobstructive kidney. Compared with Sham rats, urine and sodium excretion after acute saline loading was significantly reduced in the postobstructive kidney. The blunted excretory responses were accompanied by lower activation of ARNA and less reflex inhibition of ERNA. Renal sensory dysfunction in the postobstructive kidney was further examined by stimulation of renal mechanoreceptors and chemoreceptors. Graded increases in intrapelvic pressure or renal pelvic perfusion with hypertonic saline solution elicited, respectively, a pressure- or concentration-dependent increase in ARNA in the control kidney of Sham rats, this response being greatly attenuated in the postobstructive kidney. Western blots showed no quantitative difference in the expression of renal pelvic neurokinin 1 (NK-1) receptors between the two groups. It was concluded that renal sensory function is impaired in the postobstructive kidney of UUO rats and that this defective activation of renal sensory receptors results in an impaired renorenal reflex, which is associated with enhanced NEP activity and catabolism of SP released in the renal pelvis and is not related to the expression of NK-1 receptor protein.

Dietary glycine and renal denervation prevents cyclosporin A-induced hydroxyl radical production in rat kidney.

Cyclosporin A (CsA) nephrotoxicity is associated with renal hypoxia and increases in free radicals in the urine. This study was designed to elucidate the mechanism of radical production caused by CsA. Pretreatment of rats with CsA (25 mg/kg, i.g.) for 5 days decreased glomerular filtration rates by 65%, an effect largely prevented by both dietary glycine (5%) or renal denervation. CsA dissolved in olive oil produced a 6-line alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (4-POBN)/free radical signal in the urine, which partitioned predominantly into the aqueous phase after chloroform extraction (i.e., it is water soluble). Dimethyl sulfoxide (DMSO) is attacked by the hydroxyl radical to produce a methyl radical; administration of CsA with [(12)C]DMSO produced two radical species in urine, one with hyperfine coupling constants similar to the 4-POBN/methyl radical adduct found in aqueous solution. CsA given with [(13)C]DMSO produced a 12-line spectrum, confirming the formation of hydroxyl radicals. The methyl radical produced by the hydroxyl radical represented 62% of radicals detected in urine but only 15% in bile. Therefore, hydroxyl radicals are produced largely in the kidney. Free radicals in urine were increased about 5-fold by CsA, an effect completely blocked by the inhibitory neurotransmitter, glycine, or by renal denervation. CsA infusion for 30 min increased efferent renal nerve activity 2-fold, and dietary glycine (5%) totally blocked this phenomenon. Taken together, these data are consistent with the hypothesis that CsA increases hydroxyl radical formation by increasing renal nerve activity resulting in vasoconstriction and hypoxia-reoxygenation. Glycine blunts the effect of CsA on the renal nerve, which explains, in part, prevention of nephrotoxicity.

Effect of acute saline volume loading on renal sympathetic nerve activity in anaesthetised fructose-fed and fat-fed rats

Experiments were conducted to investigate the effects of activation of cardiopulmonary vagal afferent nerve endings by acute saline volume expansion on sympathetic efferent renal nerve activity in anaesthetised fat-fed and fructose-fed Wistar rats. Four weeks of fat feeding caused obesity in the Wistar rats which was associated with a mild elevation in blood pressure (118±4 mmHg vs. 105±1 mmHg in the lean control rats, P<0.05). Fructose feeding in Wistar rats for 4 weeks also elicited an elevation of blood pressure (113±4 mmHg, P<0.05) and plasma glucose levels (6.3±0.3 mmol/l vs. 4.0±0.3 mmol/l lean control rats, P<0.01). The fat-fed rats displayed a higher basal renal sympathetic nerve activity (RSNA) value when compared with the lean rats (3.9±0.4 mV/s vs. 2.8±0.4 mV/s, P<0.05) whereas the RSNA levels were similar in all the other rat groups. The power spectral analysis of RSNA showed the basal values of percentage power at heart rate frequency were significantly higher in Wistars fed ad lib ( P<0.01), rats fed on fructose for 2 or 4 weeks ( P<0.01 and P<0.05, respectively) and fat-fed rats ( P<0.01) when compared to the lean diet-controlled rats. Acute volume expansion (10% body wt) over 40 min caused efferent renal sympatho-inhibition in all the animal groups. The pattern and magnitude of response in MAP, RSNA, and power spectral analysis parameters to the volume expansion were similar in the lean control rats, the Wistar and fructose fed rats but was greater in the fat-fed rats ( P<0.05) as compared to the lean control rat. The profile of the reduction in percentage power at heart rate frequency to volume expansion was greater ( P<0.05) in the fat-fed rat than in the lean control rats. The present data demonstrates that the reflex efferent renal sympatho-inhibition to volume expansion was impaired in the diet-induced obese rat but not in the fructose fed rats. This suggests that a defect in the neuro-humoral regulation of kidney control of extracellular fluid volume is present which may contribute to the mild hypertension in the obese rat.

Electrophysiological evidence of ipsilateral reno–renal reflexes in the cat

To verify the existence of ipsilateral reno–renal reflexes we studied the effect of surgical denervation of one kidney on the ipsilateral efferent renal nerve activity (ERNA), in the absence of contralateral afferent renal nerve activity. Thus the ipsilateral renal denervation was performed 1 h later than the contralateral renal denervation. The experiments were done on 9 anesthetized cats. Arterial pressure, urine flow rate (UFR) of both kidneys and ERNA to the ipsilateral kidney were measured. All variables were monitored during a 3 min control period and for 13 min after either contralateral and ipsilateral renal denervations. ERNA significantly increased (+20±9%) and UFR concomitantly decreased (−11±10%) after the surgical denervation of the contralateral kidney which showed an increase (+91±19%) in UFR. The subsequent ipsilateral denervation caused a significant increase in UFR (+117±25%) and ERNA (79±23%) of the same kidney, while on the opposite side UFR did not change. During the two procedures, arterial pressure did not change. Our data demonstrate the existence of ipsilateral reno–renal reflexes that exert a tonic inhibitory effect on ipsilateral ERNA.

Bradykinin and protein kinase C activation fail to stimulate renal sensory neurons in hypertensive rats.

In normotensive rats, renal sensory receptor activation by increased ureteral pressure results in increased ipsilateral afferent renal nerve activity, decreased contralateral efferent renal nerve activity, and contralateral diuresis and natriuresis, a contralateral inhibitory renorenal reflex response. In spontaneously hypertensive rats (SHR), increasing ureteral pressure fails to increase afferent renal nerve activity. The nature of the inhibitory renorenal reflexes indicates that an impairment of the renorenal reflexes would contribute to the increased efferent renal nerve activity in SHR. We therefore examined whether there was a general decrease in the responsiveness of renal sensory receptors in SHR by comparing the afferent renal nerve activity responses to bradykinin in SHR and Wistar-Kyoto rats (WKY). In WKY, renal pelvic perfusion with bradykinin at 4, 19, 95, and 475 micromol/L increased afferent renal nerve activity by 1066 +/- 704, 2127 +/- 1121, 3517 +/- 1225, and 4476 +/- 1631% x second (area under the curve of afferent renal nerve activity versus time). In SHR, bradykinin at 4 to 95 micromol/L failed to increase afferent renal nerve activity. Bradykinin at 475 micromol/L increased afferent renal nerve activity in only 6 of 10 SHR. In WKY, renal pelvic perfusion with the phorbol ester 4beta-phorbol 12,13-dibutyrate, known to activate protein kinase C, resulted in a peak afferent renal nerve activity response of 24 +/- 4%. However, 4beta-phorbol 12,13-dibutyrate failed to increase afferent renal nerve activity in SHR. These findings demonstrate decreased responsiveness of renal pelvic sensory receptors to bradykinin in SHR. The impaired afferent renal nerve activity responses to bradykinin in SHR may be due to a lack of protein kinase C activation or a defect in the intracellular signaling mechanisms distal to protein kinase C activation.