scholarly journals α2A-Adrenoceptors Modulate Renal Sympathetic Neurotransmission and Protect against Hypertensive Kidney Disease

2020 ◽  
Vol 31 (4) ◽  
pp. 783-798 ◽  
Author(s):  
Lydia Hering ◽  
Masudur Rahman ◽  
Henning Hoch ◽  
Lajos Markó ◽  
Guang Yang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Knockout Mice ◽  
Renal Denervation ◽  
Renin Angiotensin System ◽  
Sympathetic Nerves ◽  
Protective Role ◽  
Renal Nerves ◽  
Wild Type ◽  
Renal Nerve

BackgroundIncreased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown.MethodsWe investigated effects of α2A-adrenoceptor–regulated renal NE release on the development of angiotensin II–dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor–knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days.ResultsUrinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor–knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor–knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor–knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor–deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor–knockout mice after renal denervation.ConclusionsOur findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.

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.

scholarly journals Coronavirus Disease (COVID)-19 and Diabetic Kidney Disease

2021 ◽  
Vol 14 (8) ◽  
pp. 751
Author(s):  
Swayam Prakash Srivastava ◽  
Rohit Srivastava ◽  
Subhash Chand ◽  
Julie E. Goodwin
Keyword(s):  
Kidney Disease ◽  
Viral Entry ◽  
Diabetic Kidney Disease ◽  
Thrombus Formation ◽  
Renin Angiotensin System ◽  
Cell Types ◽  
Protective Role ◽  
Kidney Cells ◽  
Diabetic Kidney

The present review describes COVID-19 severity in diabetes and diabetic kidney disease. We discuss the crucial effect of COVID-19-associated cytokine storm and linked injuries and associated severe mesenchymal activation in tubular epithelial cells, endothelial cells, and macrophages that influence neighboring cell homeostasis, resulting in severe proteinuria and organ fibrosis in diabetes. Altered microRNA expression disrupts cellular homeostasis and the renin-angiotensin-system, targets reno-protective signaling proteins, such as angiotensin-converting enzyme 2 (ACE2) and MAS1 receptor (MAS), and facilitates viral entry and replication in kidney cells. COVID-19-associated endotheliopathy that interacts with other cell types, such as neutrophils, platelets, and macrophages, is one factor that accelerates prethrombotic reactions and thrombus formation, resulting in organ failures in diabetes. Apart from targeting vital signaling through ACE2 and MAS, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are also associated with higher profibrotic dipeptidyl transferase-4 (DPP-4)-mediated mechanisms and suppression of AMP-activated protein kinase (AMPK) activation in kidney cells. Lowered DPP-4 levels and restoration of AMPK levels are organ-protective, suggesting a pathogenic role of DPP-4 and a protective role of AMPK in diabetic COVID-19 patients. In addition to standard care provided to COVID-19 patients, we urgently need novel drug therapies that support the stability and function of both organs and cell types in diabetes.

Role of the renal nerves in blood pressure in male and female SHR

2006 ◽  
Vol 290 (2) ◽  
pp. R341-R344 ◽  
Author(s):  
Radu Iliescu ◽  
Licy L. Yanes ◽  
William Bell ◽  
Terry Dwyer ◽  
Ovidiu C. Baltatu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sexual Dimorphism ◽  
Renal Denervation ◽  
Renin Angiotensin System ◽  
Sympathetic Nerves ◽  
Female Rats ◽  
Renal Nerves ◽  
Pulse Interval ◽  
Male And Female ◽  
Spontaneously Hypertensive

Female spontaneously hypertensive rats (SHR) have lower blood pressures than males. The renin-angiotensin system plays an important role in the sexual dimorphism of blood pressure in SHR. The sympathetic nervous system can stimulate renin release, and, therefore, the present study was performed to determine whether the renal sympathetic nerves play a role in the sexual dimorphism of blood pressure in SHR. Male and female SHR underwent bilateral kidney denervation or sham surgery, and, 2 wk later, mean arterial pressure (MAP) and pulse interval were recorded, and baroreflex sensitivity (BRS) was measured by the sequence technique. Left ventricle index (LVI) was also calculated. MAP was higher in sham-operated males than females (182 ± 5 vs. 169 ± 4 mmHg; P < 0.01), but, despite the higher MAP in males, LVI was significantly greater in female rats. BRS was not different between sham-operated male and female SHR. Following bilateral renal denervation, MAP was decreased by a similar percentage (8–10%) in males (169 ± 2 mmHg) and females (152 ± 3 mmHg), whereas LVI was reduced only in female SHR. BRS was not altered by renal denervation in either sex. These data indicate that renal nerves play a role in the control of blood pressure in SHR independent of sex, but do not play a role in mediating the sex differences in blood pressure.

Is the chronically denervated kidney supersensitive to catecholamines?

2002 ◽  
Vol 282 (2) ◽  
pp. R603-R610 ◽  
Author(s):  
Rohit Ramchandra ◽  
Carolyn J. Barrett ◽  
Sarah-Jane Guild ◽  
Simon C. Malpas
Keyword(s):  
Renal Function ◽  
Sympathetic Nerves ◽  
Renal Nerves ◽  
Apparent Magnitude ◽  
Ang Ii ◽  
Renal Nerve ◽  
Chronic Denervation ◽  
Over Time ◽  
Renal Sympathetic

One method for discerning the role of the renal sympathetic nerves in the regulation of renal function has been to chronically denervate one kidney. One concern with this approach is that increased renal responsiveness to plasma levels of norepinephrine may develop over time. This may reduce the apparent magnitude of the effect of the renal nerves or indeed completely mask their effect. In the present experiment, we used the rabbit unilateral denervated kidney model to examine the acute renal blood flow responses to phenylephrine to determine if there were differences between the responses in chronically denervated kidneys compared with either intact or acutely denervated kidneys. In addition, we examined the responses in rabbits that had been made hypertensive using a continuous infusion of ANG II for 7 wk. We found that chronic denervation did not result in increased renal responsiveness to phenylephrine compared with either the intact or acutely denervated kidney, suggesting that differences in renal function between renal nerve-intact and -denervated kidneys observed in previous studies are unlikely to be confounded by supersensitivity. These results suggest that the unilateral denervated kidney model is a valid model to study the role of the renal nerves in the regulation of renal function.

Neuronal regulation of renal function: A model system for nervous system interactions

1992 ◽  
Vol 70 (5) ◽  
pp. 733-734 ◽  
Author(s):  
J. Michael Wyss
Keyword(s):  
Nervous System ◽  
Renal Function ◽  
Renal Disease ◽  
Easy Access ◽  
Renal Nerves ◽  
Clinical Consequence ◽  
Nerve Activity ◽  
Renal Nerve ◽  
Renal Nerve Activity

The kidney is the most highly innervated peripheral organ, and both the excretory and endocrine functions of the kidney are regulated by renal nerve activity. The kidney plays a dominant role in body fluid homeostasis, blood ionic concentration, and pH and thereby contributes importantly to systemic blood pressure control. Early studies suggested that the neural-renal interactions were responsible only for short-term adjustments in renal function, but more recent studies indicate that the renal nerves may be a major contributor to chronic renal defects leading to established hypertension and (or) renal disease. The neural-renal interaction is also of considerable interest as a model to elucidate the interplay between the nervous system and peripheral organs, since there is abundant anatomical and physiological information characterizing the renal nerves. The investigator has easy access to the renal nerves and the neural influence on renal function is directly quantifiable both in vivo and in vitro. In this symposium that was presented at the 1990 annual convention of the Society for Neuroscience in St. Louis, Missouri, three prominent researchers evaluate the most recent progress in understanding the interplay between the nervous system and the kidney and explore how the results of these studies relate to the broader questions concerning the nervous system's interactions.First, Luciano Barajas examines the detailed anatomy of the intrarenal distribution of the efferent and afferent renal nerves along the nephron and vasculature, and he evaluates the physiological role of each of the discrete components of the innervation. His basic science orientation combined with his deep appreciation of the clinical consequence of the failure of neural-renal regulation enhances his discussion of the anatomy. Ulla C. Kopp discusses the role of the renorenal reflex, which alters renal responses following stimulation of the contralateral kidney. She also considers her recent findings that efferent renal nerve activity can directly modify sensory feedback to the spinal cord from the kidney. Finally, J. Michael Wyss examines the functional consequences of neural control of the kidney in health and disease. Although the nervous system has often been considered as only an acute regulator of visceral function, current studies into hypertension and renal disease suggest that neural-renal dysfunction may be an important contributor to chronic diseases.Together, these presentations examine most of the recent advances in the area of neural-renal interactions and point out how these data form a basis for future research into neuronal interactions with all visceral organs. The relative simplicity of the neural-renal interaction makes this system an important model with which to elucidate all neural-peripheral and neural-neural interactions.

Lack of effect of chronic renal denervation on altered sodium reabsorption during increased ureteral pressure

1980 ◽  
Vol 58 (5) ◽  
pp. 477-483 ◽  
Author(s):  
D. R. Wilson ◽  
M. Cusimano ◽  
U. Honrath
Keyword(s):  
Isotonic Saline ◽  
Urine Osmolality ◽  
Tubular Reabsorption ◽  
Renal Nerves ◽  
Sodium Reabsorption ◽  
Nerve Activity ◽  
Renal Nerve ◽  
Water Excretion ◽  
Renal Nerve Activity

The role of the renal nerves in the altered sodium reabsorption which occurs during increased ureteral pressure was studied using clearance techniques in anaesthetized rats undergoing diuresis induced by isotonic saline infusion. In rats with a sham denervated kidney, an ipsilateral increase in ureteral pressure to 20 cm H2O resulted in a marked and significant decrease in sodium and water excretion, increased fractional sodium reabsorption, and increased urine osmolality with no significant change in glomerular filtration rate. A similar significant ipsilateral increase in tubular reabsorption of sodium occurred in rats with chronically denervated kidneys during increased ureteral pressure. The changes in tubular reabsorption were rapidly reversible after return of ureteral pressure to normal. These experiments indicate that enhanced tubular reabsorption of sodium during an ipsilateral increase in ureteral pressure is not mediated by increased renal nerve activity. During the antinatriuresis of increased ureteral pressure there was a decrease in the fractional reabsorption of sodium from the opposite normal kidney. The role of the renal nerves in this compensatory change in function in the opposite kidney was studied in two further groups of animals. The renal response to a contralateral increase in ureteral pressure was similar in denervated and sham-denervated kidneys. The results indicate that altered renal nerve activity, through ipsilateral or contralateral renorenal reflexes, is not responsible for the changes in tubular reabsorption of sodium which occur during increased ureteral pressure induced by partial ureteral obstruction.

scholarly journals ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19

2020 ◽  
Vol 134 (22) ◽  
pp. 3047-3062
Author(s):  
Koichi Yamamoto ◽  
Hikari Takeshita ◽  
Hiromi Rakugi
Keyword(s):  
Skeletal Muscle ◽  
Transmembrane Protein ◽  
Renin Angiotensin System ◽  
Protective Role ◽  
Potential Contribution ◽  
Angiotensin Converting Enzyme 2 ◽  
Multiple Organs ◽  
Potential Association ◽  
Entry Receptor

Abstract Angiotensin converting enzyme-2 (ACE2) is a multifunctional transmembrane protein recently recognised as the entry receptor of the virus causing COVID-19. In the renin–angiotensin system (RAS), ACE2 cleaves angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), which is considered to exert cellular responses to counteract the activation of the RAS primarily through a receptor, Mas, in multiple organs including skeletal muscle. Previous studies have provided abundant evidence suggesting that Ang 1-7 modulates multiple signalling pathways leading to protection from pathological muscle remodelling and muscle insulin resistance. In contrast, there is relatively little evidence to support the protective role of ACE2 in skeletal muscle. The potential contribution of endogenous ACE2 to the regulation of Ang 1-7-mediated protection of these muscle pathologies is discussed in this review. Recent studies have suggested that ACE2 protects against ageing-associated muscle wasting (sarcopenia) through its function to modulate molecules outside of the RAS. Thus, the potential association of sarcopenia with ACE2 and the associated molecules outside of RAS is also presented herein. Further, we introduce the transcriptional regulation of muscle ACE2 by drugs or exercise, and briefly discuss the potential role of ACE2 in the development of COVID-19.

scholarly journals Regulation of the cognitive aging process by the transcriptional repressor RP58

2021 ◽  
Author(s):  
Tomoko Tanaka ◽  
Shinobu Hirai ◽  
Hiroyuki Manabe ◽  
Kentaro Endo ◽  
Hiroko Shimbo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Knockout Mice ◽  
Cognitive Aging ◽  
Critical Role ◽  
Harmful Effect ◽  
Transcriptional Repressor ◽  
Repair Pathway ◽  
Wild Type

Aging involves a decline in physiology which is a natural event in all living organisms. An accumulation of DNA damage contributes to the progression of aging. DNA is continually damaged by exogenous sources and endogenous sources. If the DNA repair pathway operates normally, DNA damage is not life threatening. However, impairments of the DNA repair pathway may result in an accumulation of DNA damage, which has a harmful effect on health and causes an onset of pathology. RP58, a zinc-finger transcriptional repressor, plays a critical role in cerebral cortex formation. Recently, it has been reported that the expression level of RP58 decreases in the aged human cortex. Furthermore, the role of RP58 in DNA damage is inferred by the involvement of DNMT3, which acts as a co-repressor for RP58, in DNA damage. Therefore, RP58 may play a crucial role in the DNA damage associated with aging. In the present study, we investigated the role of RP58 in aging. We used RP58 hetero-knockout and wild-type mice in adolescence, adulthood, or old age. We performed immunohistochemistry to determine whether microglia and DNA damage markers responded to the decline in RP58 levels. Furthermore, we performed an object location test to measure cognitive function, which decline with age. We found that the wild-type mice showed an increase in single-stranded DNA and gamma-H2AX foci. These results indicate an increase in DNA damage or dysfunction of DNA repair mechanisms in the hippocampus as age-related changes. Furthermore, we found that, with advancing age, both the wild-type and hetero-knockout mice showed an impairment of spatial memory for the object and increase in reactive microglia in the hippocampus. However, the RP58 hetero-knockout mice showed these symptoms earlier than the wild-type mice did. These results suggest that a decline in RP58 level may lead to the progression of aging.

scholarly journals Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

2020 ◽  
Author(s):  
Benjamin Ng ◽  
Anissa A. Widjaja ◽  
Sivakumar Viswanathan ◽  
Jinrui Dong ◽  
Sonia P. Chothani ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Lung Fibroblasts ◽  
Loss Of Function ◽  
Wild Type ◽  
Reduced Body ◽  
Body Weights ◽  
Show Evidence ◽  
Similarities And Differences ◽  
The Impact

AbstractGenetic loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and craniosynostosis. The impact of genetic LOF in IL11 has not been characterized. We generated IL11-knockout (Il11-/-) mice, which are born in normal Mendelian ratios, have normal hematological profiles and are protected from bleomycin-induced lung fibro-inflammation. Noticeably, baseline IL6 levels in the lungs of Il11-/- mice are lower than those of wild-type mice and are not induced by bleomycin damage, placing IL11 upstream of IL6. Lung fibroblasts from Il11-/- mice are resistant to pro-fibrotic stimulation and show evidence of reduced autocrine IL11 activity. Il11-/- female mice are infertile. Unlike Il11ra1-/- mice, Il11-/- mice do not have a craniosynostosis-like phenotype and exhibit mildly reduced body weights. These data highlight similarities and differences between LOF in IL11 or IL11RA while establishing further the role of IL11 signaling in fibrosis and stromal inflammation.

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