scholarly journals Endothelin contributes to blunted renal autoregulation observed with a high-salt diet

2015 ◽  
Vol 309 (8) ◽  
pp. F687-F696 ◽  
Author(s):  
Robert C. Fellner ◽  
Zhengrong Guan ◽  
Anthony K. Cook ◽  
David M. Pollock ◽  
Edward W. Inscho
Keyword(s):  
Receptor Activation ◽  
High Salt ◽  
Sprague Dawley ◽  
Dietary Salt ◽  
Renal Autoregulation ◽  
Sprague Dawley Rats ◽  
Afferent Arterioles

Autoregulation of renal blood flow (RBF) is an essential function of the renal microcirculation that has been previously shown to be blunted by excessive dietary salt. Endogenous endothelin 1 (ET-1) is increased following a high-salt (HS) diet and contributes to the control of RBF but the differential effects of ET-1 on renal microvessel autoregulation in response to HS remain to be established. We hypothesized that a HS diet increases endothelin receptor activation in normal Sprague-Dawley rats and blunts autoregulation of RBF. The role of ET-1 in the blunted autoregulation produced by a HS diet was assessed in vitro and in vivo using the blood-perfused juxtamedullary nephron preparation and anesthetized rats, respectively. Using highly selective antagonists, we observed that blockade of either ETA or ETB receptors was sufficient to restore normal autoregulatory behavior in afferent arterioles from HS-fed rats. Additionally, normal autoregulatory behavior was restored in vivo in HS-fed rats by simultaneous ETA and ETB receptor blockade, whereas blockade of ETB receptors alone showed significant improvement of normal autoregulation of RBF. Consistent with this observation, autoregulation of RBF in ETB receptor-deficient rats fed HS was similar to both ETB-deficient rats and transgenic control rats on normal-salt diets. These data support the hypothesis that endogenous ET-1, working through ETB and possibly ETA receptors, contributes to the blunted renal autoregulatory behavior in rats fed a HS diet.

scholarly journals Chronic Microcystin-LR Exposure Induces Hepatocarcinogenesis via Increased Gankyrin in Vitro and in Vivo

2018 ◽  
Vol 49 (4) ◽  
pp. 1420-1430 ◽  
Author(s):  
Lixiong He ◽  
Yujing Huang ◽  
Qiaonan Guo ◽  
Hui Zeng ◽  
Chuanfen Zheng ◽  
...  
Keyword(s):  
Low Dose ◽  
Soft Agar ◽  
Tumor Formation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
L02 Cells ◽  
Insight Into

Background/Aims: Our recent study indicated that the serum microcystin-LR (MC-LR) level is positively linked to the risk of human hepatocellular carcinoma (HCC). Gankyrin is over-expressed in cancers and mediates oncogenesis; however, whether MC-LR induces tumor formation and the role of gankyrin in this process is unclear. Methods: We induced malignant transformation of L02 liver cells via 35 passages with exposure to 1, 10, or 100 nM MC-LR. Wound healing, plate and soft agar colony counts, and nude mice tumor formation were used to evaluate the tumorigenic phenotype of MC-LR-treated cells. Silencing gankyrin was used to confirm its function. We established a 35-week MC-LR exposure rat model by twice weekly intraperitoneal injection with 10 μg/kg body weight. In addition, 96 HCC patients were tested for tumor tissue gankyrin expression and serum MC-LR levels. Results: Chronic low-dose MC-LR exposure increased proliferation, mobility, clone and tumor formation abilities of L02 cells as a result of gankyrin activation, while silencing gankyrin inhibited the carcinogenic phenotype of MC-LR-treated cells. MC-LR also induced neoplastic liver lesions in Sprague-Dawley rats due to up-regulated gankyrin. Furthermore, a trend of increased gankyrin was observed in humans exposed to MC-LR. Conclusion: These results suggest that MC-LR induces hepatocarcinogenesis in vitro and in vivo by increasing gankyrin levels, providing new insight into MC-LR carcinogenicity studies.

scholarly journals Afferent arteriolar vasodilator effect of adenosine predominantly involves adenosine A2B receptor activation

2010 ◽  
Vol 299 (2) ◽  
pp. F310-F315 ◽  
Author(s):  
Ming-Guo Feng ◽  
L. Gabriel Navar
Keyword(s):  
Receptor Activation ◽  
Receptor Blocker ◽  
Maximum Effect ◽  
Sprague Dawley ◽  
Afferent Arterioles ◽  
Vasodilator Action ◽  
Renal Vascular ◽  
Arteriolar Diameter

Adenosine is an important paracrine agent regulating renal vascular tone via adenosine A1 and A2 receptors. While A2B receptor message and protein have been localized to preglomerular vessels, functional evidence on the role of A2B receptors in mediating the vasodilator action of adenosine on afferent arterioles is not available. The present study determined the role of A2B receptors in mediating the afferent arteriolar dilation and compared the effects of A2B and A2A receptor blockade on afferent arterioles. We used the rat in vitro blood-perfused juxtamedullary nephron technique combined with videomicroscopy. Single afferent arterioles of Sprague-Dawley rats were visualized and superfused with solutions containing adenosine or adenosine A2 receptor agonist (CV-1808) along with adenosine A2B and A2A receptor blockers. Adenosine (10 μmol/l) caused modest constriction and subsequent superfusion with SCH-58261 (SCH), an A2A receptor blocker, at concentrations up 10 μmol/l elicited only slight additional decreases in afferent arteriolar diameter with maximum effect at a concentration of 1 μmol/l (−11.0 ± 2.5%, n = 6, P < 0.05). However, superfusion of adenosine-treated vessels with MRS-1754 (MRS), an A2B receptor blocker, elicited greater decreases in afferent arteriolar diameter (−26.0 ± 4.7%, n = 5, P < 0.01). SCH did not significantly augment the adenosine-mediated afferent constriction elicited by MRS; however, adding MRS after SCH caused further significant vasoconstriction. Superfusion with CV-1808 dilated afferent arterioles (17.2 ± 2.4%, n = 6, P < 0.01). This effect was markedly attenuated by MRS (−22.6 ± 2.0%, n = 5, P < 0.01) but only slightly reduced by SCH (−9.0 ± 1.1%, n = 5, P < 0.05) and completely prevented by adding MRS after SCH (−24.7 ± 1.8%, n = 5, P < 0.01). These results indicate that, while both A2A and A2B receptors are functionally expressed in juxtamedullary afferent arterioles, the powerful vasodilating action of adenosine predominantly involves A2B receptor activation, which counteracts A1 receptor-mediated vasoconstriction.

scholarly journals Role of RFRP-3 in the development of cold stress-induced polycystic ovary phenotype in rats

2018 ◽  
Vol 239 (1) ◽  
pp. 81-91 ◽  
Author(s):  
V Squicciarini ◽  
R Riquelme ◽  
K Wilsterman ◽  
G E Bentley ◽  
H E Lara
Keyword(s):  
Cold Stress ◽  
Polycystic Ovary ◽  
Follicular Development ◽  
Sprague Dawley ◽  
Ovarian Steroid ◽  
Sprague Dawley Rats ◽  
Mrna Expression Analysis

RFamide-related peptide (RFRP-3) is a regulator of GnRH secretion from the brain, but it can also act in human ovary to influence steroidogenesis. We aimed to study the putative local role of RFRP-3 in the ovary and its potential participation in the development of a polycystic ovary phenotype induced by chronic sympathetic stress (cold stress). We used adult Sprague–Dawley rats divided into control and stressed groups. In both groups, we studied the effect of intraovarian exposure to RFRP-3 on follicular development and plasma ovarian steroid concentrations. We also tested the effect of RFRP-3 on ovarian steroid production in vitro. Chronic in vivo intraovarian exposure to RFRP-3 decreased basal testosterone concentrations and cold stress-induced progesterone production by the ovary. In vitro, RFRP-3 decreased hCG-induced ovarian progesterone and testosterone secretion. Immunohistochemistry and mRNA expression analysis showed a decrease in Rfrp and expression of its receptor in the ovary of stressed rats, a result which is in line with the increased testosterone levels found in stressed rats. In vivo application of RFRP-3 recovered the low levels of secondary and healthy antral follicles found in stressed rats. Taken together, our data indicate a previously unknown response of hypothalamic and ovarian RFRP-3 to chronic cold stress, influencing ovarian steroidogenesis and follicular dynamics. Thus, it is likely that RFRP-3 modulation in the ovary is a key component of development of the polycystic ovary phenotype.

scholarly journals Renal medullary ETB receptors produce diuresis and natriuresis via NOS1

2008 ◽  
Vol 294 (5) ◽  
pp. F1205-F1211 ◽  
Author(s):  
Daisuke Nakano ◽  
Jennifer S. Pollock ◽  
David M. Pollock
Keyword(s):  
Renal Medulla ◽  
Urinary Sodium Excretion ◽  
Receptor Activation ◽  
No Production ◽  
Sprague Dawley ◽  
Receptor Stimulation ◽  
Water Excretion ◽  
Sprague Dawley Rats

Endothelin-1 (ET-1) plays an important role in the regulation of salt and water excretion in the kidney. Considerable in vitro evidence suggests that the renal medullary ETB receptor mediates ET-1-induced inhibition of electrolyte reabsorption by stimulating nitric oxide (NO) production. The present study was conducted to test the hypothesis that NO synthase 1 (NOS1) and protein kinase G (PKG) mediate the diuretic and natriuretic effects of ETB receptor stimulation in vivo. Infusion of the ETB receptor agonist sarafotoxin S6c (S6c: 0.45 μg·kg−1·h−1) in the renal medulla of anesthetized, male Sprague-Dawley rats markedly increased the urine flow (UV) and urinary sodium excretion (UNaV) by 67 and 120%, respectively. This was associated with an increase in medullary cGMP content but did not affect blood pressure. In addition, S6c-induced diuretic and natriuretic responses were absent in ETB receptor-deficient rats. Coinfusion of NG-propyl-l-arginine (10 μg·kg−1·h−1), a selective NOS1 inhibitor, suppressed S6c-induced increases in UV, UNaV, and medullary cGMP concentrations. Rp-8-Br-PET-cGMPS (10 μg·kg−1·h−1) or RQIKIWFQNRRMKWKK-LRK5H-amide (18 μg·kg−1·h−1), a PKG inhibitor, also inhibited S6c-induced increases in UV and UNaV. These results demonstrate that renal medullary ETB receptor activation induces diuretic and natriuretic responses through a NOS1, cGMP, and PKG pathway.

Metalloendopeptidases EC 3.4.24.15/16 regulate bradykinin activity in the cerebral microvasculature

2003 ◽  
Vol 284 (6) ◽  
pp. H1942-H1948 ◽  
Author(s):  
M. Ursula Norman ◽  
Rebecca A. Lew ◽  
A. Ian Smith ◽  
Michael J. Hickey
Keyword(s):  
Specific Inhibitor ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Cerebral Microvasculature ◽  
Microvessel Permeability ◽  
The Brain ◽  
Cerebral Microvessel

Bradykinin is a vasoactive peptide that has been shown to increase the permeability of the cerebral microvasculature to blood-borne macromolecules. The two zinc metalloendopeptidases EC 3.4.24.15 (EP 24.15) and EC 3.4.24.16 (EP 24.16) degrade bradykinin in vitro and are highly expressed in the brain. However, the role that these enzymes play in bradykinin metabolism in vivo remains unclear. In the present study, we investigated the role of EP 24.15 and EP 24.16 in the regulation of bradykinin-induced alterations in microvascular permeability. Permeability of the cerebral microvasculature was assessed in anesthetized Sprague-Dawley rats by measuring the clearance of 70-kDa FITC dextran from the brain. Inhibition of EP 24.15 and EP 24.16 by the specific inhibitor N-[1-( R, S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr- p-aminobenzoate (JA-2) resulted in the potentiation of bradykinin-induced increases in cerebral microvessel permeability. The level of potentiation was comparable to that achieved by the inhibition of angiotensin-converting enzyme. These findings provide the first evidence of an in vivo role for EP 24.15/EP 24.16 in brain function, specifically in regulating alterations in microvessel permeability induced by exogenous bradykinin.

T-type calcium channels in the regulation of afferent and efferent arterioles in rats

2004 ◽  
Vol 286 (2) ◽  
pp. F331-F337 ◽  
Author(s):  
Ming-Guo Feng ◽  
Ming Li ◽  
L. Gabriel Navar
Keyword(s):  
Perfusion Pressure ◽  
Channel Blockers ◽  
Channel Blockade ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Arteriolar Resistance ◽  
Afferent Arterioles ◽  
Constrictor Response

L-type Ca2+ channels predominantly influence preglomerular arterioles, but there is less information regarding the role of T-type Ca2+ channels in regulating the renal microvasculature. We compared the effects of T- and L-type channel blockade on afferent and efferent arterioles using the in vitro blood-perfused juxtamedullary nephron preparation. Single afferent or efferent arterioles of Sprague-Dawley rats were visualized and superfused with solutions containing Ca2+ channel blockers. We confirmed that L-type channel blockade with diltiazem dilates afferent arterioles but has no significant effects on efferent arterioles. In contrast, T-type channel blockade with pimozide (10 μmol/l) or mibefradil (1 μmol/l) dilated both afferent (26.8 ± 3.4 and 24.6 ± 1.9%) and efferent (19.2 ± 2.9 and 19.1 ± 4.8%) arterioles. Adding diltiazem did not significantly augment the dilation of afferent arterioles elicited by pimozide and mibefradil, and adding pimozide after diltiazem likewise did not elicit further vasodilation. Diltiazem blocked the depolarization-induced afferent arteriolar constriction elicited by 55 mM KCl; however, the constrictor response to KCl remained intact during treatment with 10 μM pimozide. Pimozide also prevented the afferent arterioles from exhibiting autoregulatory-mediated constrictor responses to increases in perfusion pressure. We conclude that T-type channel blockers dilate efferent arterioles as well as afferent arterioles and diminish afferent arteriolar autoregulatory responses to changes in perfusion pressure. To the extent that these agents exert their effects primarily on T-type Ca2+ channels in our experimental setting, these results indicate that T-type channels are functionally expressed in juxtamedullary afferent and efferent arterioles and may act cooperatively with L-type channels to regulate afferent arteriolar resistance. Because L-type channels are not functionally expressed in efferent arterioles, T-type channels may be particularly significant in the regulation of efferent arteriolar function.

Cytochrome C suppresses renal accumulation and nephrotoxicity of polymyxin B

2018 ◽  
Vol 38 (2) ◽  
pp. 193-200 ◽  
Author(s):  
Z-D Li ◽  
J Luo ◽  
L-H Jia ◽  
X-Y Wang ◽  
Z-K Xun ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Polymyxin B ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
C 30 ◽  
C 50

The receptor megalin plays an important role in the accumulation of polymyxin B (PMB) in renal cells in vitro. This study aimed to examine the effects of cytochrome c (cyto c), a typical megalin ligand, on renal accumulation and nephrotoxicity of PMB in vivo. Thirty Sprague-Dawley rats were randomly divided into the vehicle control group, PMB group, PMB + cyto c 50, 100, or 200 mg/kg group, respectively, and were treated with intravenous cyto c 30 min before the administration of PMB 4.0 mg/kg once a day for consecutive 5 days. On the 4th day after administration, 24 h urine was collected to determine N-acetyl-β-D-glucosaminidase excretion. Six hours after the last injection on the 5th day, kidneys were harvested to assay PMB concentration and observe pathological alterations, and blood samples were collected to assay serum creatinine (SCr), blood urea nitrogen (BUN), and blood β2-microglobulin (β2-MG) levels. Cyto c 50, 100, and 200 mg/kg decreased the accumulation of PMB in the kidney by 18.5%, 39.1% ( p < 0.01), and 36.8% ( p < 0.01), respectively, and reduced 24 h N-acetyl-β-D- glucosaminidase excretion by 22.5% ( p < 0.05), 40.4% ( p < 0.01), and 40.4% ( p < 0.01), respectively. Kidney pathological damage induced by PMB was markedly reduced by cyto c 100 mg/kg and 200 mg/kg. However, there were no significant differences in SCr, BUN, and blood β2-MG levels among the groups. These results indicated that cyto c may inhibit the renal accumulation and nephrotoxicity of PMB in a rat model, further proving the role of megalin in the accumulation of PMB.

scholarly journals Upregulation of SIRT1 and FOXO3a Contributes to The Protective Role of Estrogen on HPH in Rats

2020 ◽  
Author(s):  
Li Wang ◽  
Yadong Yuan ◽  
Xiaowei Gong ◽  
Jianjun Mao
Keyword(s):  
Pulmonary Artery ◽  
Protective Role ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Pulmonary Vascular Remodeling ◽  
Sprague Dawley Rats ◽  
Sirt1 Activator

Abstract Background: SIRT1 has anti-proliferation effects on cells through regulating the expression and activity of FOXOs. Estrogen (E2) has protective effects against hypoxic pulmonary hypertension (HPH), but the involvement of SIRT1 and FOXOs in the proliferation of pulmonary artery smooth muscle cells (PASMCs) and contribution to the effects of E2 on HPH are poorly understood. To use E2 to explore the roles of SIRT1 and FOXO3a in the pathogenesis and progression of HPH and pulmonary vascular remodeling (PVR) in vivo and in vitro.Methods: Female Sprague-Dawley rats with bilateral ovariectomy were randomized to normoxia, normoxia+E2, hypoxia, and hypoxia+E2. Serum E2 levels, hemodynamic, and pulmonary vascular pathomorphology were assessed. The anti-proliferation effect of E2 was determined in human PASMCs under hypoxia/normoxia. Immunohistochemistry, western blotting, and real-time PCR were used to assess SIRT1, FOXO3a, and PCNA in rat pulmonary artery and hPASMCs. SIRT1 activity was assayed.Results: Hypoxia increased mean pulmonary artery pressure (mPAP), medial width of pulmonary arterioles, right ventricular hypertrophy index (RVHI), decreased expression SIRT1 and FOXO3a and increased PCNA expression in rats; E2 alleviated these changes. In vitro, E2 significantly inhibited hypoxia-induced hPASMCs proliferation, associated with improvements in SIRT1 and FOXO3a expression, consistent with the in vivo results. SIRT1 inhibition attenuated the effects of E2 on hPASMCs proliferation and the expression of FOXO3a. A SIRT1 activator mimicked the effects of E2 on hPASMCs proliferation and the expression of FOXO3a.Conclusions: Upregulation of SIRT1 and FOXO3a contributes to the protective role of estrogen on HPH in rats, as supported by in vitro results using hPASMCs.

scholarly journals Leptin induces the expression of tumorigenic genes in the gastric mucosa of male Sprague-Dawley rats

2018 ◽  
Vol 243 (14) ◽  
pp. 1118-1124 ◽  
Author(s):  
Faizatul Isyraqiah ◽  
Methil K Kutty ◽  
Damayanthi Durairajanayagam ◽  
Norita Salim ◽  
Harbindarjeet Singh
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Gastric Carcinogenesis ◽  
Control Group ◽  
Sprague Dawley ◽  
Gastric Cancer Cells ◽  
Sprague Dawley Rats

Leptin promotes the growth of gastric cancer cells in vitro. It is, however, unknown if leptin induces gastric cancer in vivo. This study therefore investigated the effect of leptin on the histology and expression of tumorigenic genes in the stomach of rats following 40 weeks of leptin treatment. Male Sprague-Dawley rats, aged 6 weeks, were randomized into control and experimental groups ( n = 8 per group). The experimental group was given intraperitoneal injections of leptin (60 µg/kg/day) once daily for 40 weeks, whereas the control group received intraperitoneal injection of an equal volume of normal saline daily. Rats were housed in polypropylene cages for the duration of the study. Body weight was measured weekly. Upon completion of treatment, rats were euthanized and their stomachs were collected for histopathological examination, microarray, and RT-qPCR. Data were analyzed using one-way ANOVA and Fisher’s exact test. On histology, one rat (12.5%) in the leptin-treated group had a large red-colored tumor nodule at the pyloric antrum of the stomach. Microscopically, stomachs of two leptin-treated rats (25%) showed hyperplasia or dysplasia. Microarray analysis revealed significant upregulation of a number of genes in the stomachs of leptin-treated rats that have been shown to be associated with tumorigenesis in other tissues, including Furin (protein maturation), Eef1a1 and Eif4g2 (translation factors), Tmed2 (vesicular trafficking), Rab7a (plasma membrane trafficking), Rfwd2 (protein degradation), Fth1 and Ftl1 (oxygen transport), Tspan8, Tspan1, Fxyd3, and Rack1 (cell migration), Pde4d (signal transduction), Nupr1 and Ybx1 (transcription factors), Ptma and Tmem134 (oncogenes), Srsf2 (mRNA maturation), and Reep5 (cell proliferation). None of the known oncogenes were, however, significantly up-regulated. In conclusion, although the overall effect of leptin on gastric carcinogenesis seems inconclusive, the findings of dysplasia and the up-regulation of some of the cancer-related genes nevertheless warrant further scrutiny on the role of leptin in gastric cancer. Impact statement Gastric cancer is the third most common cause of death due to cancer in the world. Obese individuals are at risk of developing gastric cancer, and the reason for this is unknown. Serum leptin levels are high in obese individuals and leptin is known to induce proliferation of gastric cancer cells in vitro. However, to date, no reports exist on the tumorigenic effects of leptin on the stomach in vivo. This study therefore determines if chronic leptin administration induces gastric carcinogenesis in non-obese rats, which might serve as a useful animal model for future studies. Although the findings are somewhat inconclusive, to our knowledge, however, this is the first study to show the up-regulation of numerous potential driver genes that highlight the potential role of leptin in the higher prevalence of gastric cancer among obese individuals. The findings certainly necessitate further scrutiny of leptin gastric cancer.

Y1- and α1-receptor control of basal hindlimb vascular tone

2004 ◽  
Vol 287 (1) ◽  
pp. R228-R233 ◽  
Author(s):  
Dwayne N. Jackson ◽  
Earl G. Noble ◽  
J. Kevin Shoemaker
Keyword(s):  
Vascular Tone ◽  
Receptor Activation ◽  
In Vivo Studies ◽  
Sprague Dawley ◽  
Vascular Conductance ◽  
Flow Profiles ◽  
Sprague Dawley Rats ◽  
Differential Flow

The role of endogenous Y1-receptor activation on skeletal muscle vasculature under baseline conditions is currently debated and no in vivo studies have been performed to address this issue. Therefore, this study was designed to address the effect of Y1-receptor and/or α1-adrenoceptor antagonism on basal hindlimb vascular conductance in male Sprague-Dawley rats in vivo. Left hindlimb vascular conductance, carotid artery mean arterial pressure, and heart rate were measured during low volume infusion of N2-(diphenylacetyl)- N-[(4-hydroxyphenyl)methyl]-d-arginine amide (BIBP3226; 100 μg/kg), prazosin (20 μg/kg), and combined blockade to the left hindlimb. Vascular conductance increased 1.5 ± 0.5 μl·min−1·mmHg−1 with BIBP3226 infusion, 1.7 ± 0.5 μl·min−1·mmHg−1 with prazosin infusion, and 4.8 ± 1.0 μl·min−1·mmHg−1 with combined blockade ( P < 0.05). Interestingly, systolic vascular conductance increased in all three conditions, but diastolic vascular conductance only increased in the two conditions where BIBP3226 was present. These data indicate that Y1-receptor activation plays an important role in the regulation of vascular conductance in the resting rat hindlimb. Furthermore, this effect was of the same magnitude as the α1-adrenoceptor contribution. The differential flow profiles following α1 blockade with and without Y1-receptor blockade supports local differences in receptor distribution.

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