scholarly journals Role of Renal Sympathetic Nerves in GLP‐1 (Glucagon‐Like Peptide‐1) Receptor Agonist Exendin‐4‐Mediated Diuresis and Natriuresis in Diet‐Induced Obese Rats

2021 ◽  
Author(s):  
Xuefei Liu ◽  
Kaushik P. Patel ◽  
Hong Zheng
Keyword(s):  
Renal Denervation ◽  
Sympathetic Nerves ◽  
Urine Flow ◽  
Obese Rats ◽  
Neprilysin Inhibition ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Expression And Activity ◽  
Renal Sympathetic

Background The gut‐derived hormone GLP‐1 (glucagon‐like peptide‐1) exerts beneficial effects against established risk factors for chronic kidney disease. GLP‐1 influences renal function by stimulating diuresis and natriuresis and thus lowering arterial blood pressure. The role of the sympathetic nervous system has been implicated as an important link between obesity with elevated arterial pressure and chronic kidney disease. The primary aim of this study was to determine the contribution of renal sympathetic nerves on intrapelvic GLP‐1‐mediated diuresis and natriuresis in high‐fat diet (HFD)‐induced obese rats. Methods and Results Obesity was induced in rats by HFD for 12 weeks, followed by either surgical bilateral renal denervation or chronic subcutaneous endopeptidase neprilysin inhibition by sacubitril for a week. Diuretic and natriuretic responses to intrapelvic administration of the GLP‐1R (GLP‐1 receptor) agonist exendin‐4 were monitored in anesthetized control and HFD rats. Renal GLP‐1R expression and neprilysin expression and activity were measured. The effects of norepinephrine on the expression of GLP‐1R and neprilysin in kidney epithelial LLC‐PK1 cells were also examined. We found that diuretic and natriuretic responses to exendin‐4 were significantly reduced in the HFD obese rats compared with the control rats (cumulative urine flow at 40 minutes, 387±32 versus 650±65 µL/gkw; cumulative sodium excretion at 40 minutes, 42±5 versus 75±10 µEq/gkw, P <0.05). These responses in the HFD rats were restored after ablation of renal nerves (cumulative urine flow at 40 minutes, 625±62 versus 387±32 µL/gkw; cumulative sodium excretion at 40 minutes, 70±9 versus 42±5 µEq/gkw, P <0.05). Renal denervation induced significant reductions in arterial pressure and heart rate responses to intrapelvic GLP‐1 in the HFD rats. Renal denervation also significantly increased the GLP‐1R expression and reduced neprilysin expression and activity in renal tissues from the HFD rats. Chronic subcutaneous neprilysin inhibition by sacubitril increased GLP‐1–induced diuretic and natriuretic effects in the HFD rats. Finally, exposure of the renal epithelial cells to norepinephrine in vitro led to downregulation of GLP‐1R expression but upregulation of neprilysin expression and activity. Conclusions These results suggest that renal sympathetic nerve activation contributes to the blunted diuretic and natriuretic effects of GLP‐1 in HFD obese rats. This study provides significant novel insight into the potential renal nerve–neprilysin–GLP‐1 pathway involved in renal dysfunction during obesity that leads to hypertension.

Renal denervation alters cardiovascular and endocrine responses to hemorrhage in conscious newborn lambs

1998 ◽  
Vol 275 (1) ◽  
pp. H285-H291 ◽  
Author(s):  
Francine G. Smith ◽  
Isam Abu-Amarah
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Renal Denervation ◽  
Plasma Renin ◽  
Sympathetic Nerves ◽  
Renal Nerves ◽  
Elevated Plasma ◽  
Baseline Levels ◽  
Renal Sympathetic

To investigate the role of renal sympathetic nerves in modulating cardiovascular and endocrine responses to hemorrhage early in life, we carried out three experiments in conscious, chronically instrumented lambs with intact renal nerves (intact; n = 8) and with bilateral renal denervation (denervated; n = 5). Measurements were made 1 h before and 1 h after 0, 10, and 20% hemorrhage. Blood pressure decreased transiently after 20% hemorrhage in intact lambs and returned to control levels. In denervated lambs, however, blood pressure remained decreased after 60 min. After 20% hemorrhage, heart rate increased from 170 ± 16 to 207 ± 18 beats/min in intact lambs but not in denervated lambs, in which basal heart rates were already elevated to 202 ± 21 beats/min. Despite an elevated plasma renin activity (PRA) measured in denervated (12.0 ± 6.4 ng ANG I ⋅ ml−1 ⋅ h−1) compared with intact lambs (4.0 ± 1.1 ng ANG I ⋅ ml−1 ⋅ h−1), the increase in PRA in response to 20% hemorrhage was similar in both groups. Plasma levels of arginine vasopressin increased from 11 ± 8 to 197 ± 246 pg/ml after 20% hemorrhage in intact lambs but remained unaltered in denervated lambs from baseline levels of 15 ± 10 pg/ml. These observations provide evidence that in the newborn, renal sympathetic nerves modulate cardiovascular and endocrine responses to hemorrhage.

Role of renal sympathetic nerves in response of the ovine fetus to volume expansion

1990 ◽  
Vol 259 (5) ◽  
pp. R1050-R1055 ◽  
Author(s):  
F. G. Smith ◽  
T. Sato ◽  
O. J. McWeeny ◽  
J. M. Klinkefus ◽  
J. E. Robillard
Keyword(s):  
Volume Expansion ◽  
Renal Denervation ◽  
Sympathetic Nerves ◽  
Renal Hemodynamics ◽  
Fetal Life ◽  
Renal Nerve ◽  
Fetal Sheep ◽  
Arterial Blood ◽  
Renal Sympathetic

To investigate the role of renal sympathetic nerves in the fetal response to hypervolemia, studies were carried out in conscious, chronically instrumented fetal sheep aged 137-142 days of gestation. Bilateral renal denervation (n = 9) or sham surgery (n = 8) was carried out under halothane anesthesia 3-6 days before experiments. Bilateral renal denervation did not alter basal fetal renal hemodynamics, glomerular filtration rate (GFR), or Na+ excretion. Volume expansion with 6% Dextran 70 (18 ml/kg) was associated with a fall in fetal hematocrit, a sustained increase in mean arterial blood pressure, and a sustained diuresis and natriuresis. There was no significant change in GFR during fetal hypervolemia from control levels of 4.51 +/- 0.74 ml/min (intact) and 4.43 +/- 0.43 ml/min (denervated). Atrial natriuretic factor increased from 144 +/- 34 to 464 +/- 134 pg/ml, and plasma renin activity decreased from 5.15 +/- 1.7 to 3.04 +/- 1.0 ng.ml-1.h-1 in intact animals, within 30 min of completion of the dextran infusion. Similar changes occurred in denervated fetuses. Plasma aldosterone levels remained constant in intact and denervated fetuses during hypervolemia at control levels of 40.8 +/- 5.4 and 59.3 +/- 8.4 pg/ml, respectively. These findings suggest that renal sympathetic nerves do not influence basal renal hemodynamics or function and do not appear to play an important role in the natriuretic response to volume expansion during fetal life. This can be explained by a low tonic renal nerve activity before birth.

Translational medicine: the antihypertensive effect of renal denervation

2010 ◽  
Vol 298 (2) ◽  
pp. R245-R253 ◽  
Author(s):  
Gerald F. DiBona ◽  
Murray Esler
Keyword(s):  
Translational Medicine ◽  
Renal Denervation ◽  
Antihypertensive Effect ◽  
Human Subjects ◽  
Sympathetic Nerves ◽  
Clinical Applications ◽  
Primary Role ◽  
Renal Innervation ◽  
Renal Sympathetic

Translational medicine is concerned with the translation of research discoveries into clinical applications for the prevention, diagnosis, and treatment of human diseases. Here we briefly review the research concerning the role of the renal sympathetic nerves (efferent and afferent) in the control of renal function, with particular reference to hypertension. The accumulated evidence is compelling for a primary role of the renal innervation in the pathogenesis of hypertension. These research discoveries led to the development of a catheter-based procedure for renal denervation in human subjects. A proof-of-principle study in patients with hypertension resistant to conventional therapy has demonstrated that the procedure is safe and produces renal denervation with sustained lowering of arterial pressure.

Pentobarbital anesthesia alters renal actions of alpha-hANP in dogs

1990 ◽  
Vol 258 (3) ◽  
pp. R616-R623 ◽  
Author(s):  
J. B. Madwed ◽  
B. C. Wang
Keyword(s):  
Sodium Excretion ◽  
Renal Denervation ◽  
Control Period ◽  
Cardiovascular Responses ◽  
Sympathetic Nerves ◽  
Control Value ◽  
Anesthetized Dogs ◽  
Renal Responses ◽  
Renal Sympathetic

The magnitude of the natriuretic response to an infusion of alpha-human atrial natriuretic peptide (alpha-hANP) has varied considerably in different studies. The greatest renal responses to alpha-hANP infusion have been observed in barbiturate-anesthetized dogs. We therefore examined the renal, hormonal, and cardiovascular responses to alpha-hANP infusion in eight female dogs, once awake and again anesthetized with pentobarbital sodium (25 mg/kg body wt). After a 20-min control period, alpha-hANP was infused at a rate of 25 ng.kg-1.min-1 for 60 min. In dogs when awake, infusion of alpha-hANP produced a significant increase in sodium excretion from a control value of 39 +/- 7 to 73 +/- 13 and 89 +/- 15 mu eq/min after 40 and 60 min. In dogs when anesthetized, infusion of alpha-hANP produced an increase in sodium excretion from 21 +/- 3 to 105 +/- 12 and 143 +/- 21 mu eq/min after 40 and 60 min. The increase in sodium excretion was significantly greater in dogs when anesthetized than when awake. We also investigated the role of the renal sympathetic nerves on these responses in six dogs after chronic bilateral renal denervation. In dogs with denervated kidneys when awake, infusion of alpha-hANP did not change sodium excretion significantly. In dogs with denervated kidneys when anesthetized, infusion of alpha-hANP significantly increased sodium excretion; however, the increase was significantly attenuated when compared with anesthetized dogs with intact kidneys. We conclude that the natriuretic response to an infusion of alpha-hANP is enhanced in dogs when anesthetized. Also, the natriuretic response was attenuated by renal denervation in dogs when anesthetized.

scholarly journals Renal denervation and CD161a immune ablation prevent cholinergic hypertension and renal sodium retention

2019 ◽  
Vol 317 (3) ◽  
pp. H517-H530 ◽  
Author(s):  
Nandita Raikwar ◽  
Cameron Braverman ◽  
Peter M. Snyder ◽  
Robert A. Fenton ◽  
David K. Meyerholz ◽  
...  
Keyword(s):  
Immune Cells ◽  
Renal Denervation ◽  
Renal Medulla ◽  
Sympathetic Nerves ◽  
Sodium Retention ◽  
Sodium Potassium ◽  
Immune Ablation ◽  
Renal Expression ◽  
Renal Sympathetic

Cholinergic receptor activation leads to premature development of hypertension and infiltration of proinflammatory CD161a+/CD68+ M1 macrophages into the renal medulla. Renal inflammation is implicated in renal sodium retention and the development of hypertension. Renal denervation is known to decrease renal inflammation. The objective of this study was to determine the role of CD161a+/CD68+ macrophages and renal sympathetic nerves in cholinergic-hypertension and renal sodium retention. Bilateral renal nerve denervation (RND) and immune ablation of CD161a+ immune cells were performed in young prehypertensive spontaneously hypertensive rat (SHR) followed by infusion of either saline or nicotine (15 mg·kg−1·day−1) for 2 wk. Immune ablation was conducted by injection of unconjugated azide-free antibody targeting rat CD161a+. Blood pressure was monitored by tail cuff plethysmography. Tissues were harvested at the end of infusion. Nicotine induced premature hypertension, renal expression of the sodium-potassium chloride cotransporter (NKCC2), increases in renal sodium retention, and infiltration of CD161a+/CD68+ macrophages into the renal medulla. All of these effects were abrogated by RND and ablation of CD161a+ immune cells. Cholinergic activation of CD161a+ immune cells with nicotine leads to the premature development of hypertension in SHR. The effects of renal sympathetic nerves on chemotaxis of CD161a+ macrophages to the renal medulla, increased renal expression of NKCC2, and renal sodium retention contribute to cholinergic hypertension. The CD161a+ immune cells are necessary and essential for this prohypertensive nicotine-mediated inflammatory response. NEW & NOTEWORTHY This is the first study that describes a novel integrative physiological interaction between the adrenergic, cholinergic, and renal systems in the development of hypertension, describing data for the role of each in a genetic model of essential hypertension. Noteworthy findings include the prevention of nicotine-mediated hypertension following successful immune ablation of CD161a+ immune cells and the necessary role these cells play in the overexpression of the sodium-potassium-chloride cotransporter (NKCC2) in the renal medulla and renal sodium retention. Renal infiltration of these cells is demonstrated to be dependent on the presence of renal adrenergic innervation. These data offer a fertile ground of therapeutic potential for the treatment of hypertension as well as open the door for further investigation into the mechanism involved in inflammation-mediated renal sodium transporter expression. Taken together, these findings suggest immune therapy, renal denervation, and, possibly, other new molecular targets as having a potential role in the development and maintenance of essential hypertension. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/cd161a-immune-cells-in-cholinergic-hypertension/ .

scholarly journals Renal sensory and sympathetic nerves reinnervate the kidney in a similar time-dependent fashion after renal denervation in rats

2013 ◽  
Vol 304 (8) ◽  
pp. R675-R682 ◽  
Author(s):  
Jan Mulder ◽  
Tomas Hökfelt ◽  
Mark M. Knuepfer ◽  
Ulla C. Kopp
Keyword(s):  
Substance P ◽  
Optical Density ◽  
Renal Denervation ◽  
Time Course ◽  
Sympathetic Nerves ◽  
Sensory Nerves ◽  
Sensory Innervation ◽  
Multiple Time ◽  
Sensory Reinnervation ◽  
Renal Sympathetic

Efferent renal sympathetic nerves reinnervate the kidney after renal denervation in animals and humans. Therefore, the long-term reduction in arterial pressure following renal denervation in drug-resistant hypertensive patients has been attributed to lack of afferent renal sensory reinnervation. However, afferent sensory reinnervation of any organ, including the kidney, is an understudied question. Therefore, we analyzed the time course of sympathetic and sensory reinnervation at multiple time points (1, 4, and 5 days and 1, 2, 3, 4, 6, 9, and 12 wk) after renal denervation in normal Sprague-Dawley rats. Sympathetic and sensory innervation in the innervated and contralateral denervated kidney was determined as optical density (ImageJ) of the sympathetic and sensory nerves identified by immunohistochemistry using antibodies against markers for sympathetic nerves [neuropeptide Y (NPY) and tyrosine hydroxylase (TH)] and sensory nerves [substance P and calcitonin gene-related peptide (CGRP)]. In denervated kidneys, the optical density of NPY-immunoreactive (ir) fibers in the renal cortex and substance P-ir fibers in the pelvic wall was 6, 39, and 100% and 8, 47, and 100%, respectively, of that in the contralateral innervated kidney at 4 days, 4 wk, and 12 wk after denervation. Linear regression analysis of the optical density of the ratio of the denervated/innervated kidney versus time yielded similar intercept and slope values for NPY-ir, TH-ir, substance P-ir, and CGRP-ir fibers (all R2 > 0.76). In conclusion, in normotensive rats, reinnervation of the renal sensory nerves occurs over the same time course as reinnervation of the renal sympathetic nerves, both being complete at 9 to 12 wk following renal denervation.

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