Abstract P472: Prorenin Independently Causes Hypertension And Renal and Cardiac Fibrosis In Cyp1a1-Prorenin Transgenic Rats

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Yufeng Huang ◽  
Guangyu Zhou ◽  
Jie Wu ◽  
Chunyan Gu ◽  
Alfred Cheung
Keyword(s):  
Cardiac Fibrosis ◽  
Heart Tissue ◽  
Female Rats ◽  
Organ Injury ◽  
Heart Weight ◽  
Diabetic Patients ◽  
Transgenic Rats ◽  
Protein Levels ◽  
Male And Female Rats ◽  
Pai 1

Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In this study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (Cyp1a1 prorenin transgenic male and female rats and nontransgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration rose from 23±6 to 208±44 (μg/ml) and MAP increased from 77±5 to 138±17 (mmHg), whereas renal prorenin/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of TGFß1, PAI-1, collagen and fibronectin. These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight. Cardiac collagen in interstitial and perivascular area was prominent, accompanied by the increases in mRNA contents of ANP, BNP, ß-MHC, TGFß1 and PAI-1 in the heart tissue. Furthermore, renal protein levels of phosphor-NF-kB-p65 and MCP-1, NAPDH oxidase and MDA, phospho-ß-catenin and phospho-Akt were dramatically increased in prorenin overexpressed rats. These results indicate that prorenin, without being converted to renin, causes arterial hypertension, renal and cardiac fibrosis independently via the induction of inflammation, oxidative stress and the ß-catenin and Akt-mediated signals.

scholarly journals Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats

2018 ◽  
Vol 132 (12) ◽  
pp. 1345-1363 ◽  
Author(s):  
Guangyu Zhou ◽  
Jie Wu ◽  
Chunyan Gu ◽  
Bin Wang ◽  
E. Dale Abel ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Female Rats ◽  
Organ Injury ◽  
Heart Weight ◽  
Diabetic Patients ◽  
Transgenic Rats ◽  
Male And Female Rats ◽  
Pai 1

Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In the present study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (cyp1a1 prorenin transgenic male and female rats and non-transgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration was increased and mean arterial pressure (MAP) increased from 80 ± 18 to 138 ± 17 (mmHg), whereas renal prorenin/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by Western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of transforming growth factor β (TGFβ) 1 (TGFβ1), plasminogen activator inhibitor-1 (PAI-1), collagen, and fibronectin (FN). These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight (HW/BW). Cardiac collagen in interstitial and perivascular regions was prominent, accompanied by the increase in mRNA contents of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-myosin heavy chain (β-MHC), TGFβ1, PAI-1, and collagen in the heart tissue. Furthermore, renal protein levels of p-NF-κB-p65 and monocyte chemoattractant protein-1 (MCP-1), NAPDH oxidases, malondialdehyde (MDA) and 8-isoprostane (8-IP), p-ERK, p-β-catenin, and p-Akt were dramatically increased in prorenin overexpressing rats. These results indicate that prorenin, without being converted into renin, causes hypertension, renal and cardiac fibrosis via the induction of inflammation, oxidative stress and the ERK, β-catenin, and Akt-mediated signals.

B74 THE EFFECTS OF ACUTE TRYPTOPHAN DEPLETION ON BDNF PROTEIN LEVELS IN BRAIN AND SERUM OF MALE AND FEMALE RATS

2005 ◽  
Vol 16 (Supplement 1) ◽  
pp. S89
Author(s):  
E.L. Van Donkelaar ◽  
L.A.W. Jans ◽  
A. Blokland ◽  
N.E.P. Deutz ◽  
G. Kenis ◽  
...  
Keyword(s):  
Female Rats ◽  
Acute Tryptophan Depletion ◽  
Tryptophan Depletion ◽  
Male And Female ◽  
Protein Levels ◽  
Male And Female Rats

Aniline and hexobarbital hydroxylases from rat lung and kidney: neither sex dependent nor inducible with phenobarbital

1982 ◽  
Vol 60 (10) ◽  
pp. 1247-1250 ◽  
Author(s):  
Janet L. Lister ◽  
Bruce B. Virgo
Keyword(s):  
Microsomal Protein ◽  
Female Rats ◽  
Rat Lung ◽  
Male And Female ◽  
Aniline Hydroxylase ◽  
Protein Levels ◽  
Male And Female Rats ◽  
Males And Females ◽  
Cytochrome P 450 ◽  
Lung And Kidney

The basal activities of aniline hydroxylase (AH), hexobarbital hydroxylase (HH), and ethylmorphine N-demethylase (ED) were measured in the 9000 × g supernatant of kidneys and lungs from male and female rats. No ED activity was detected in any tissue although all tissues N-demethylated three other substrates. The activities of AH and HH were not sex dependent in either kidney or lung. Similarly, pulmonary and renal microsomal protein concentrations were independent of sex. In addition, cytochrome P-450 levels in the kidney were the same in males and females (pulmonary P-450 was not measured). The pulmonary hydroxylases were more active than the renal enzymes in both sexes. In males, phenobarbital (ip, 50 rng∙kg−1∙day−1 for 3 days) failed to induce AH or HH in either kidney or lung; it did not increase the weight or microsomal protein levels of these organs and it also failed to increase renal P-450. Thus, the basal activities of AH and HH in lungs and kidneys are not different in male and female rats and are not increased by phenobarbital.

Selected Contribution: Estrogen receptor-α antisense decreases brain estrogen receptor levels and affects ventilation in male and female rats

2001 ◽  
Vol 91 (4) ◽  
pp. 1886-1892 ◽  
Author(s):  
Shashita R. Inamdar ◽  
Kathleen M. Eyster ◽  
Evelyn H. Schlenker
Keyword(s):  
Estrogen Receptor ◽  
Aspartic Acid ◽  
Estrogen Receptor Α ◽  
Neonatal Rat ◽  
Female Rats ◽  
Antisense Oligodeoxynucleotide ◽  
Protein Levels ◽  
Ventilatory Responses ◽  
Rat Pups ◽  
Male And Female Rats

We hypothesized that administration of an antisense oligodeoxynucleotide (ODN) to estrogen receptor (ER)-α mRNA decreases the ER protein in the neonatal rat brain, alters the sex-specific ventilatory responses to aspartic acid in rats, and counteracts the effects of testosterone proportionate (TP) in females. One-day-old rat pups were injected intraventricularly with vehicle, antisense ER ODN, or scrambled ODN control. Additional groups of females received TP or vehicle and one of the three treatments. Brain ER protein levels were decreased by 65% at 6 h and 35% at 24 h after antisense ODN. Aspartic acid decreased ventilation in all groups of weanling males and females except ER ODN-treated females and TP-vehicle-treated females. Aspartic acid decreased ventilation in all groups of adult females except those given TP and in males. Weanling ER ODN-treated rats were shorter and weighed less than controls. Only adult ER ODN-treated males exhibited these traits. Thus neonatal ER affects aspartic acid modulation of breathing and body growth in a sex-specific and developmental manner.

scholarly journals ADAMTS13/VWF Axis Potentially Contributes to Diabetic Nephropathy By Regulating PAI-1 Levels

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2240-2240
Author(s):  
Nirav Dhanesha ◽  
Anil K. Chauhan
Keyword(s):  
Body Weight ◽  
Diabetic Nephropathy ◽  
Renal Injury ◽  
Weight Ratio ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Body Weight Ratio ◽  
Renal Hypertrophy ◽  
Protein Levels ◽  
Pai 1

Abstract Background and objective: ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type I repeats-13) cleaves von Willebrand factor (VWF), a large multimeric protein that plays an important role in hemostasis and thrombosis. Severe deficiency or very low levels of ADAMTS13 in presence of external stimuli results in accumulation of thrombogenic ultra large VWF multimers (which are released from activated endothelium) known to trigger thrombotic microangiopathy. Activated endothelium/dysfunction is a prominent feature of diabetic nephropathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy. Significantly reduced ADAMTS13 and increased plasma VWF levels have been found in diabetic patients with nephropathy. Although major site of ADAMTS13 synthesis is liver, ADAMTS13 is also expressed by podocytes in normal renal cortex. It remains unknown, however, whether VWF and ADAMTS13 imbalance plays a causal role in development of nephropathy in diabetic patients or rather is simply an associate marker of disease status, possibly secondary to endothelial function. We performed experiments in genetic models to determine whether ADAMTS13 and VWF axis contributes to diabetic nephropathy. Methods : Male, 8-10 weeks old wild-type (WT), Adamts13-/- and Vwf-/- mice were made diabetic by injecting multiple low doses of streptozotocin (60 mg/kg, i.p. for five consecutive days). Successful diabetes induction was tested after 2 weeks by measuring blood glucose. Mice having blood glucose levels above 300 mg/dL were included in the study. Controls were nondiabetic littermate mice treated with citrate buffer. The extent of renal injury was evaluated after 28 weeks of diabetes induction by measuring albuminuria and kidney to body weight ratio. Renal hypertrophy and extracellular matrix deposition was quantified by hematoxylin and immunostaining. PAI-1 mRNA and protein levels were measured by real time quantitative RT-PCR and ELISA. Results: Adamts13- /- diabetic mice exhibited significantly increased kidney to body weight ratio (P<0.05 vs. WT diabetic mice). Urine albuminuria, an index of renal injury was significantly elevated in Adamts13-/- diabetic mice (P<0.05 vs. WT diabetic mice). Increased renal injury in Adamts13-/- diabetic mice was concomitant with increased renal hypertrophy and extracellular matrix (ECM) deposition within glomeruli (P<0.05 vs. WT diabetic mice). Murine studies have shown that PAI-1 contributes to diabetic nephropathy by regulating TGF-beta and ECM deposition. A positive association exists between increased PAI-1 levels in glomeruli and microangiopathy in patients with diabetic nephropathy. We determined whether ADAMTS13 deficiency-induced microangiopathy in glomeruli increases PAI-1 levels. Adamts13-/- diabetic mice exhibited increased PAI-1 mRNA and protein levels (P<0.05 vs. WT diabetic mice). VWF remains the only known substrate of ADAMTS13 and increased plasma VWF levels have been associated with diabetic nephropathy. We determined the role of VWF in diabetic nephropathy. Vwf-/- diabetic mice exhibited significantly decreased kidney weight/body weight ratio, less urinary albuminuria, decreased kidney PAI-1 expression levels concomitant with improved kidney morphological changes (P<0.05 vs. WT diabetic mice). Conclusion : These findings provide experimental evidence for the first time that ADAMTS13/VWF axis potentially contributes to diabetic nephropathy, most likely by regulating PAI-1 levels. Disclosures No relevant conflicts of interest to declare.

Role of insulin on jejunal PepT1 expression and function regulation in diabetic male and female rats

2010 ◽  
Vol 88 (7) ◽  
pp. 753-759 ◽  
Author(s):  
Asdghig H. Der-Boghossian ◽  
Sara R. Saad ◽  
Claudine Perreault ◽  
Chantale Provost ◽  
Danielle Jacques ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Insulin Treatment ◽  
Mrna Level ◽  
Female Rats ◽  
Male Rats ◽  
Influx Rate ◽  
Male And Female ◽  
Protein Levels ◽  
Male And Female Rats ◽  
Pept1 Mrna

The aim of this study was to determine whether the jejunal oligopeptide transporter PepT1 is regulated by insulin and whether this regulation is sex-dependent in type 1 diabetic rats. PepT1 expression, real-time polymerase chain reaction, and Western blots were performed using jejunal segments from 4 groups of male and female rats: normal (nondiabetic), insulin-treated nondiabetic, streptozotocin (STZ)-induced diabetic (type 1 diabetes), and insulin-treated diabetic models. Furthermore, the same segments from all groups underwent perfusion to assess uptake of the dipeptide glycylsarcosine through PepT1. Our results showed that insulin treatment of nondiabetic female rats decreased blood glucose level but did not affect nondiabetic male rats. In both male and female diabetic rats, insulin did not completely decrease blood glucose level. Insulin treatment decreased PepT1 mRNA level in nondiabetic male rats and increased mRNA level in nondiabetic female rats without affecting the PepT1 protein level in either sex. Inducing diabetes with STZ increased PepT1 mRNA and protein levels in female rats; however, in diabetic male rats, the increase in mRNA level was accompanied by a decrease in PepT1 protein level. Treatment of diabetic male rats with insulin partially reversed the effect of diabetes on PepT1 mRNA and protein levels, whereas the same treatment completely restored both PepT1 mRNA and protein to control levels in insulin-treated diabetic female rats. In both nondiabetic male and female rats, insulin treatment had no effect on PepT1 influx rate, and STZ treatment decreased the transporter influx rate. Treatment of diabetic male and female rats with insulin significantly increased PepT1 influx rate; however, complete recovery was found only in diabetic female rats. These results clearly show that insulin and diabetes affected blood glucose level as well as PepT1 activity, expression, and protein levels in a sex-dependent manner. These results suggest that a factor, probably estrogen, could be responsible for the sex-dependent effects of diabetes and insulin in PepT1 level and activity.

scholarly journals Procollagen C-Proteinase Enhancer 1 (PCPE-1) is a marker of myocardial fibrosis and impaired cardiac function in a murine model of pressure overload

2021 ◽  
Author(s):  
Priscillia Lagoutte ◽  
Alexandra Oudot ◽  
Mélissa Dussoyer ◽  
Victor Goncalves ◽  
Mélanie Guillemin ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Cardiac Fibrosis ◽  
Volume Fraction ◽  
Interstitial Fibrosis ◽  
Heart Function ◽  
Heart Diseases ◽  
Pressure Overload ◽  
Heart Tissue ◽  
Extracellular Matrix Protein ◽  
Protein Levels

Abstract(1)AimsProcollagen C-proteinase enhancer 1 (PCPE-1) is an extracellular matrix protein and a major regulator of fibrillar collagen biosynthesis. Previous work has shown that its abundance is often increased in the context of tissue repair and fibrosis. The present study was designed to evaluate its potential as a biomarker of myocardial interstitial fibrosis (MIF), a well-established pathogenic pathway leading to heart failure.(2)Methods and ResultsCardiac fibrosis was induced in rats using an optimized model of chronic pressure overload triggered by angiotensin II and Nω-nitro-L-arginine methyl ester (L-NAME). All treated animals suffered from heart hypertrophy and the increase in heart collagen volume fraction (CVF), evidenced by histology and 68Ga-Collagelin uptake, confirmed the development of cardiac fibrosis. Functional analysis by simultaneous PET-MRI further showed that our model closely reflected the pathological features seen in human MIF, including left ventricle thickening and diastolic dysfunction associated with decreased ejection fraction. PCPE-1 mRNA and protein levels were augmented by factors of 3.4 and 6.1 respectively in the heart tissue of treated rats. Moreover, protein abundance was well-correlated with CVF (r=0.92, p<0.0001) and PCPE-1 immuno-detection mainly localized the protein to fibrotic areas. Finally, PCPE-1 plasma levels measured by ELISA were increased in fibrotic rats compared to controls.(3)ConclusionTogether, our findings demonstrate that PCPE-1 levels in the heart and circulation tightly reflect the cardiac fibrosis status and heart function impairment in rats and suggest that it could be a very useful marker to monitor human heart diseases leading to fibrosis.

scholarly journals Plasminogen activator inhibitor-1 (PAI-1) is cardioprotective in mice by maintaining microvascular integrity and cardiac architecture

Blood ◽  
2010 ◽  
Vol 115 (10) ◽  
pp. 2038-2047 ◽  
Author(s):  
Zhi Xu ◽  
Francis J. Castellino ◽  
Victoria A. Ploplis
Keyword(s):  
Plasminogen Activator ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Plasminogen Activator Inhibitor ◽  
Transforming Growth Factor Β ◽  
Heart Tissue ◽  
Matrix Remodeling ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Although the involvement of plasminogen activator inhibitor-1 (PAI-1) in fibrotic diseases is well documented, its role in cardiac fibrosis remains controversial. The goal of this study was to determine the effect of a PAI-1 deficiency (PAI-1−/−) on the spontaneous development of cardiac fibrosis. PAI-1−/− mice developed pervasive cardiac fibrosis spontaneously with aging, and these mice displayed progressively distorted cardiac architecture and markedly reduced cardiac function. To mechanistically elucidate the role of PAI-1 in cardiac fibrosis, 12-week-old mice were chosen to study the biologic events leading to fibrosis. Although fibrosis was not observed at this early age, PAI-1−/− hearts presented with enhanced inflammation, along with increased microvascular permeability and hemorrhage. A potent fibrogenic cytokine, transforming growth factor-β (TGF-β), was markedly enhanced in PAI-1−/− heart tissue. Furthermore, the expression levels of several relevant proteases associated with tissue remodeling were significantly enhanced in PAI-1−/− hearts. These results suggest that PAI-1 is cardioprotective, and functions in maintaining normal microvasculature integrity. Microvascular leakage in PAI-1−/− hearts may provoke inflammation, and predispose these mice to cardiac fibrosis. Therefore, a PAI-1 deficiency contributes to the development of cardiac fibrosis by increasing vascular permeability, exacerbating local inflammation, and increasing extracellular matrix remodeling, an environment conducive to accelerated fibrosis.

Effects of sex hormones on development of physiological and pathological cardiac hypertrophy in male and female rats

1990 ◽  
Vol 259 (3) ◽  
pp. H866-H871 ◽  
Author(s):  
A. Malhotra ◽  
P. Buttrick ◽  
J. Scheuer
Keyword(s):  
Cardiac Hypertrophy ◽  
Sex Hormones ◽  
Renal Hypertension ◽  
Estrogen Therapy ◽  
Female Rats ◽  
Heart Weight ◽  
Normal Heart ◽  
Myosin Isoenzyme ◽  
Pathological Cardiac Hypertrophy ◽  
Male And Female Rats

Previous studies have demonstrated a role for sex hormones in maintaining normal heart weight and myosin isoenzyme balance in the rat. To determine if sex hormones were necessary to elicit cardiac adaptations to the chronic loads of swimming or hypertension, female rats were gonadectomized (X) and then exposed either to a chronic swimming program (Sw) or to renal hypertension for 8-10 wk. Because gonadectomy in females increased heart and body weight, separate groups of food-restricted sedentary and Sw gonadectomized females (XFR) were included. Swimming resulted in significant increases in both heart weight and in the percent ventricular V1 isomyosin in female controls (C), X, and XFR. Hypertension was studied in C, X, and X with estrogen replacement. Cardiac hypertrophy developed in all groups, but estrogen therapy attenuated the decline in percent V1 isomyosin in both normotensive and hypertensive X animals. Swimming, which is generally not associated with cardiac hypertrophy in males, was also studied in that sex. Gonadectomy did not alter either the heart weight or the myosin isoenzyme response to Sw, although testosterone replacement in gonadectomized males restored ventricular V1 myosin levels to or above normal. Measures of serum thyroid levels and of myocardial catecholamines failed to demonstrate a causal relationship between these hormones and the various results. Therefore, although sex hormones are important for maintaining normal heart weights and myosin isoenzyme balance in rats, they do not appear to be important in the adaptations hearts exhibit when exposed to physiological or pathological loads.

Daily exercise and gender influence arterial baroreflex regulation of heart rate and nerve activity

1996 ◽  
Vol 271 (5) ◽  
pp. H1840-H1848 ◽  
Author(s):  
C. Y. Chen ◽  
S. E. DiCarlo
Keyword(s):  
Heart Rate ◽  
Female Rats ◽  
Male Rats ◽  
Heart Weight ◽  
Arterial Baroreflex ◽  
Nerve Activity ◽  
Male And Female ◽  
Gender Influence ◽  
Male And Female Rats ◽  
And Gender

The influence of daily spontaneous running (DSR) and gender on the arterial baroreflex regulation of heart rate (HR) and lumbar sympathetic nerve activity (LSNA) was examined in 13 male [7 sedentary (SED) and 6 DSR] and 12 female (6 SED and 6 DSR) Sprague-Dawley rats. After 8-9 wk of DSR or SED control, all animals were chronically instrumented with right femoral venous and left carotid arterial catheters and electrodes around the lumbar sympathetic trunk. DSR resulted in an increase in heart weight-to-body weight ratio (P = 0.001) in male and female rats and resting bradycardia in male rats (P = 0.001). Arterial baroreflex function was examined by ramp increases (1.25 +/- 0.07 mmHg/s) and decreases (1.47 mmHg/s) in arterial pressure. DSR attenuated the arterial baroreflex regulation of LSNA in a similar manner in female and male rats. DSR reduced the range (32 and 29% for female and male rats, respectively), maximum (26 and 21% for female and male rats, respectively), and maximum gain (Gmax; 46 and 17% for female and male rats, respectively). In contrast, there was a gender influence on the arterial baroreflex regulation of HR. For example, SED female rats had a higher Gmax (40%) than SED male rats. Furthermore, DSR altered the arterial baroreflex regulation of HR differently in male and female rats. DSR female rats had a reduced Gmax (38%), range (25%), and maximum (12%), whereas DSR male rats had a reduced maximum (17%) and minimum (23%). These results demonstrate that DSR attenuated the arterial baroreflex regulation of LSNA in a similar manner in female and male rats. In contrast, DSR altered the arterial baroreflex regulation of HR differently in female and male rats.

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