scholarly journals Relaxin and Castration in Male Mice Protect from, but Testosterone Exacerbates, Age-Related Cardiac and Renal Fibrosis, Whereas Estrogens Are an Independent Determinant of Organ Size

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 188-199 ◽  
Author(s):  
Tim D. Hewitson ◽  
Chongxin Zhao ◽  
Belinda Wigg ◽  
Sin Wai Lee ◽  
Evan R. Simpson ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Gene Knockout ◽  
Hormone Replacement ◽  
Weight Ratio ◽  
Organ Size ◽  
Wild Type ◽  
Estradiol Treatment ◽  
Collagen Concentration ◽  
Age Related ◽  
17Β Estradiol

This study determined the effects of castration and hormone replacement therapy on the age-related cardiac and renal pathology of male relaxin gene-knockout (RlnKO) and age-matched wild-type (RlnWT) mice and that of aged male aromatase knockout (ArKO) mice, which lack estrogens and have 5–10 times the androgen levels of male wild-type mice. One-month-old RlnWT and RlnKO mice were bilaterally gonadectomized or sham operated and maintained until 12 months. Subgroups of castrated animals received testosterone or 17β-estradiol treatment from 9 to 12 months. Male ArKO mice and aromatase wild-type mice were aged to 12 months. Collected heart and kidney tissues were assessed for changes in organ size and fibrosis. Castration reduced body, heart, left ventricle, and kidney weights in both RlnKO and RlnWT mice, and the cardiac/renal fibrosis that was seen in sham RlnKO animals (all P < 0.05 vs. respective sham). Testosterone normalized organ weights and organ weight to body weight ratio of castrated animals and increased cardiac/renal collagen concentration to levels measured in or beyond that of sham RlnKO mice (all P < 0.05 vs. respective castrated mice). Furthermore, expression of TGF-β1, mothers against decapentaplegic homolog 2 (Smad2), and myofibroblast differentiation paralleled the above changes (all P < 0.05 vs. respective castrated mice), whereas matrix metalloproteinase-13 was decreased in testosterone-treated RlnKO mice. Conversely, 17β-estradiol only restored changes in organ size. Consistent with these findings, intact ArKO mice demonstrated increased cardiac/renal fibrosis in the absence of changes in organ size. These findings suggest that relaxin and castration protect, whereas androgens exacerbate, cardiac and renal fibrosis during ageing, whereas estrogens, in synergy with relaxin, regulates age-related changes in organ size.

Beneficial effects of isometric strength training on endothelial dysfunction in rats

2006 ◽  
Vol 31 (5) ◽  
pp. 621-630 ◽  
Author(s):  
Hélène Figard ◽  
Vincent Gaume ◽  
Fabienne Mougin ◽  
Céline Demougeot ◽  
Alain Berthelot
Keyword(s):  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Isometric Exercise ◽  
Ovariectomized Rats ◽  
Daily Injection ◽  
Sprague Dawley ◽  
Estradiol Treatment ◽  
Sedentary Group ◽  
Age Related ◽  
17Β Estradiol

Using female 4-week-old Sprague–Dawley rats, we investigated the effects of 14 weeks of progressive strength isometric training on endothelium dysfunction after estrogen deficiency. We also proposed possible mechanism(s) by which such training acted on endothelium-dependent vasodilation in thoracic aortic rings. Rats were randomly divided into 4 groups of 8 rats: a sham operated group, an ovariectomized sedentary group receiving 17β-estradiol vehicle s.c. daily, an ovariectomized sedentary group receiving a daily injection of 20 µg·kg–1 17β-estradiol s.c., and an ovariectomized exercised group receiving daily s.c. vehicle. Vascular reactivity of aortic rings have been evaluated by a cumulative dose of acetylcholine (ACh), in the presence or absence of l-NAME (N-nitro-l-arginine methyl ester), indomethacin, thapsigargin, iberiotoxin, apamin, and tetraethylammonium. Ovariectomy markedly decreased the relaxation caused by ACh, whereas 17β-estradiol treatment induced a significant increase in the relaxation elicited by ACh. Isometric exercise enhanced relaxation due to ACh. This enhancement was attenuated in the presence of l-NAME, indomethacin, thapsigargin, iberiotoxin, and apamin. Our data indicated, for the first time, that the endothelium-dependent relaxant response to ACh was markedly improved in trained ovariectomized rats. This increased vasodilation is mediated by nitric oxide, cyclooxygenase, sarco-endoplasmic reticulum Ca2+-ATPase pathways, and endothelium-derived hyperpolarizing factor. Finally, this study suggested that resistance training may provide benefits in addressing vascular dysfunction consequent to a decline in estrogen levels after menopause. However, any benefits for age-related vascular dysfunction remain to be demonstrated.

scholarly journals Aging and Loss of Circulating 17β-Estradiol Alters the Alternative Splicing of ERβ in the Female Rat Brain

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4187-4199 ◽  
Author(s):  
Cody L. Shults ◽  
Elena Pinceti ◽  
Yathindar S. Rao ◽  
Toni R. Pak
Keyword(s):  
Alternative Splicing ◽  
Rna Polymerase Ii ◽  
Topoisomerase I ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Hormone Replacement ◽  
Female Rats ◽  
Female Rat ◽  
Age Related ◽  
17Β Estradiol

Loss of circulating 17β-estradiol (E2) that occurs during menopause can have detrimental effects on cognitive function. The efficacy of hormone replacement therapy declines as women become farther removed from the menopausal transition, yet the molecular mechanisms underlying this age-related switch in E2 efficacy are unknown. We hypothesized that aging and varying lengths of E2 deprivation alters the ratio of alternatively spliced estrogen receptor (ER)β isoforms in the brain of female rats. Further, we tested whether changes in global transcriptional activity and splicing kinetics regulate the alternative splicing of ERβ. Our results revealed brain region-specific changes in ERβ alternative splicing in both aging and E2-deprivation paradigms and showed that ERβ could mediate E2-induced alternative splicing. Global transcriptional activity, as measured by phosphorylated RNA polymerase II, was also regulated by age and E2 in specific brain regions. Finally, we show that inhibition of topoisomerase I resulted in increased ERβ2 splice variant expression.

Effects of Hormone Replacement Therapy on Plasma and Tissue Fibrinolytic Activity in a Rat Model of Surgically Induced Menopause

2014 ◽  
Vol 37 (2) ◽  
pp. 85 ◽  
Author(s):  
Ata Topcuoglu ◽  
Mustafa Albayrak ◽  
Hayriye Erman ◽  
Huriye Balci ◽  
Mesut Karakus ◽  
...  
Keyword(s):  
Hormone Replacement Therapy ◽  
Oral Administration ◽  
Replacement Therapy ◽  
Plasminogen Activator ◽  
Brain Tissue ◽  
Fibrinolytic Activity ◽  
Hormone Replacement ◽  
17Β Estradiol ◽  
Surgically Induced ◽  
Pai 1

Purpose: The purpose of this study was to analyze the effects of estrogen deficiency and hormone replacement therapy (HRT) on fibrinolytic activity in a rat mode of surgically-induced menopause. Methods: Twelve-week-old, sexually mature female Sprague-Dawley rats, each weighing 200–250 g, were randomly divided into four groups: (1) sham-operated group, (2) ovariectomy group, (3) ovariectomy group followed by oral administration of daily 17β-estradiol (0.02 mg/kg/day) (E2) + norethisterone acetate (0.01 mg/kg/day), and (4) ovariectomy group followed by oral administration of daily 17β-estradiol (0.01 mg/kg/day) + drospirenone (0.02 mg/kg/day). Tissue plasminogen activator (tPA) antigen, plasminogen activator inhibitor-1 (PAI-1) antigen, and PAI-1/tPA levels were measured as markers of fibrinolysis in plasma and liver and brain tissue. Results: Compared with sham-operated rats, ovariectomized rats showed higher levels of fibrinolytic activity; however, the increased fibrinolytic activity in plasma and liver tissue was significantly reduced by HRT regimens. No change was observed in the levels of fibrinolytic activity in brain tissue. Conclusions: HRT showed beneficial effects by decreasing fibrinolytic activity related to surgically-induced menopause. Short-term HRT treatment was associated with a shift in the procoagulant-anticoagulant balance toward a procoagulant state.

scholarly journals Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy

2021 ◽  
Vol 22 (13) ◽  
pp. 7222
Author(s):  
Yoshinori Okamoto ◽  
Hideto Jinno ◽  
Shinji Itoh ◽  
Shinya Shibutani
Keyword(s):  
Hormone Replacement Therapy ◽  
Replacement Therapy ◽  
Hormone Replacement ◽  
Metabolic Activation ◽  
Ovariectomized Rats ◽  
Estrogenic Potential ◽  
Carcinogenic Potential ◽  
Induced Tumors ◽  
Carcinogenic Effects ◽  
17Β Estradiol

Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17β-estradiol (2-ClE2) or 4-chloro-17β-estradiol (4-ClE2) was implanted subcutaneously for 52 weeks into August Copenhagen Irish (ACI) rats, a preferred animal model for human breast cancer. 17β-Estradiol (E2) frequently induced mammary tumors while both 2-ClE2 and 4-ClE2 did not. Their 17α-ethinyl forms, thought to be orally active estrogens, were also synthesized. Neither 2-chloro-17α-ethinylestradiol (2-ClEE2) nor 4-chloro-17α-ethinylestradiol (4-ClEE2) induced tumors. The less carcinogenic effects were supported by histological examination of mammary glands of ACI rats treated with the chlorinated estrogens. A chlorine atom positioned at the 2- or 4-position of E2 may prevent the metabolic activation, resulting in reducing the carcinogenicity. 2-ClE2 and 4-ClE2 administered subcutaneously and 2-ClEE2 and 4-ClEE2 given orally to ovariectomized rats all showed uterotrophic potency, albeit slightly weaker than that of E2. Our results indicate that less carcinogenic chlorinated estrogens retaining estrogenic potential could be safer alternatives to the carcinogenic estrogens now in use for HRT.

scholarly journals Sex Differences in the Triad of Acquired Sensorineural Hearing Loss

2021 ◽  
Vol 22 (15) ◽  
pp. 8111
Author(s):  
Kuang-Hsu Lien ◽  
Chao-Hui Yang
Keyword(s):  
Hearing Loss ◽  
Sex Differences ◽  
Sexual Dimorphism ◽  
Sensorineural Hearing Loss ◽  
Hormone Replacement ◽  
Modern Society ◽  
Sensorineural Hearing ◽  
Drug Induced ◽  
Age Related ◽  
Age Related Hearing Loss

The triad of noise-generated, drug-induced, and age-related hearing loss is the major cause of acquired sensorineural hearing loss (ASNHL) in modern society. Although these three forms of hearing loss display similar underlying mechanisms, detailed studies have revealed the presence of sex differences in the auditory system both in human and animal models of ASNHL. However, the sexual dimorphism of hearing varies among noise-induced hearing loss (NIHL), ototoxicity, and age-related hearing loss (ARHL). Importantly, estrogen may play an essential role in modulating the pathophysiological mechanisms in the cochlea and several reports have shown that the effects of hormone replacement therapy on hearing loss are complex. This review will summarize the clinical features of sex differences in ASNHL, compare the animal investigations of cochlear sexual dimorphism in response to the three insults, and address how estrogen affects the auditory organ at molecular levels.

scholarly journals In Vivo 17β-Estradiol Treatment Contributes to Podocyte Actin Stabilization in Female db/db Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (12) ◽  
pp. 5888-5895 ◽  
Author(s):  
Paola Catanuto ◽  
Alessia Fornoni ◽  
Simone Pereira-Simon ◽  
Fayi Wu ◽  
Kerry L. Burnstein ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Transcriptional Activation ◽  
Cell Types ◽  
Proper Function ◽  
Estradiol Treatment ◽  
Diabetic Glomerulosclerosis ◽  
Podocyte Damage ◽  
Rac1 Activity ◽  
17Β Estradiol

Abstract We recently showed that 17β-estradiol (E2) treatment ameliorated type 2 diabetic glomerulosclerosis in mice in part by protecting podocyte structure and function. Progressive podocyte damage is characterized by foot process effacement, vacuolization, detachment of podocytes from the glomerular basement membrane, and apoptosis. In addition, podocytes are highly dependent on the preservation of their actin cytoskeleton to ensure proper function and survival. Because E2 administration prevented podocyte damage in our study on diabetic db/db mice and has been shown to regulate both actin cytoskeleton and apoptosis in other cell types and tissues, we investigated whether actin remodeling and apoptosis were prevented in podocytes isolated from E2-treated diabetic db/db mice. We performed G-actin/F-actin assays, Western analysis for Hsp25 expression, Ras-related C3 botulinum toxin substrate 1 (Rac1) activity, and apoptosis assays on previously characterized podocytes isolated from both in vivo-treated placebo and E2 female db/db mice. We found that in vivo E2 protects against a phenotype change in the cultured podocytes characterized by a percent increase of F-actin vs. G-actin, suppression of Hsp25 expression and transcriptional activation, increase of Rac1 activity, and decreased apoptotic intermediates. We conclude from these studies that E2 treatment protects against podocyte damage and may prevent/reduce diabetes-induced kidney disease.

scholarly journals Effects of TRPC6 Inactivation on Glomerulosclerosis and Renal Fibrosis in Aging Rats

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 856
Author(s):  
Eun Young Kim ◽  
Stuart E. Dryer
Keyword(s):  
Renal Function ◽  
Protective Effect ◽  
Renal Fibrosis ◽  
Transient Receptor Potential ◽  
Smooth Muscle Actin ◽  
Receptor Potential ◽  
Sprague Dawley ◽  
Age Related ◽  
Sprague Dawley Rats ◽  
Transient Receptor

Canonical transient receptor potential 6 (TRPC6) channels have been implicated in familial and acquired forms of focal and segmental glomerulosclerosis (FSGS) in patients and animal models, as well as in renal fibrosis following ureteral obstruction in mice. Aging also evokes declines in renal function owing to effects on almost every renal compartment in humans and rodents. Here, we have examined the role of TRPC6 in driving inflammation and fibrosis during aging in Sprague-Dawley rats. This was assessed in rats with non-functional TRPC6 channels owing to CRISPR-Cas9 deletion of a portion of the ankyrin repeat domain required for the assembly of functional TRPC6 channels (Trpc6del/del rats). Wild-type littermates (Trpc6wt/wt rats) were used as controls. Animals were evaluated at 2 months and 12 months of age. There was no sign of kidney disease at 2 months of age, regardless of genotype. However, by 12 months of age, all rats examined showed declines in renal function associated with albuminuria, azotemia and increased urine excretion of β2–microglobulin, a marker for proximal tubule pathology. These changes were equally severe in Trpc6wt/wt and Trpc6del/del rats. We also observed age-related increases in renal cortical expression of markers of fibrosis (α-smooth muscle actin and vimentin) and inflammation (NLRP3 and pro-IL−1β), and there was no detectable protective effect of TRPC6 inactivation. Tubulointerstitial fibrosis assessed from histology also appeared equally severe in Trpc6wt/wt and Trpc6del/del rats. By contrast, glomerular pathology, blindly scored from histological sections, suggested a significant protective effect of TRPC6 inactivation, but only within the glomerular compartment.

scholarly journals The Alopecia Areata Phenotype Is Induced by the Water Avoidance Stress Test In cchcr1-Deficient Mice

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 840
Author(s):  
Qiaofeng Zhao ◽  
Satoshi Koyama ◽  
Nagisa Yoshihara ◽  
Atsushi Takagi ◽  
Etsuko Komiyama ◽  
...  
Keyword(s):  
Alopecia Areata ◽  
Gene Knockout ◽  
Stress Test ◽  
Coiled Coil ◽  
Risk Haplotype ◽  
Gene Expression Microarray ◽  
Wild Type ◽  
Gene Knockout Mice ◽  
Deficient Mice ◽  
Gene Expression Microarray Analysis

We recently discovered a nonsynonymous variant in the coiled-coil alpha-helical rod protein 1 (CCHCR1) gene within the alopecia areata (AA) risk haplotype. We also reported that the engineered mice with this risk allele exhibited. To investigate more about the involvement of the CCHCR1 gene in AA pathogenesis, we developed an AA model using C57BL/6N cchcr1 gene knockout mice. In this study, mice (6–8 weeks) were divided into two groups: cchcr1−/− mice and wild-type (WT) littermates. Both groups were subjected to a water avoidance stress (WAS) test. Eight weeks after the WAS test, 25% of cchcr1−/− mice exhibited non-inflammatory foci of alopecia on the dorsal skin. On the other hand, none of wild-type littermates cause hair loss. The foci resembled human AA in terms of gross morphology, trichoscopic findings and histological findings. Additionally, gene expression microarray analysis of cchcr1−/− mice revealed abnormalities of hair related genes compared to the control. Our results strongly suggest that CCHCR1 is associated with AA pathogenesis and that cchcr1−/− mice are a good model for investigating AA.

scholarly journals KCNJ11 knockout morula re-engineered by stem cell diploid aggregation

2008 ◽  
Vol 364 (1514) ◽  
pp. 269-276 ◽  
Author(s):  
Timothy J Nelson ◽  
Almudena Martinez-Fernandez ◽  
Andre Terzic
Keyword(s):  
Metabolic Flux ◽  
Ex Vivo ◽  
Gene Knockout ◽  
Embryonic Stem ◽  
Adaptive Behaviour ◽  
Wild Type ◽  
New Paradigm ◽  
Cell Functions ◽  
Dependent Cell ◽  
Channel Dependent

KCNJ11 -encoded Kir6.2 assembles with ATP-binding cassette sulphonylurea receptors to generate ATP-sensitive K + (K ATP ) channel complexes. Expressed in tissues with dynamic metabolic flux, these evolutionarily conserved yet structurally and functionally unique heteromultimers serve as high-fidelity rheostats that adjust membrane potential-dependent cell functions to match energetic demand. Genetic defects in channel subunits disrupt the cellular homeostatic response to environmental stress, compromising organ tolerance in the adult. As maladaptation characterizes malignant K ATP channelopathies, establishment of platforms to examine progression of K ATP channel-dependent adaptive behaviour is warranted. Chimeras provide a powerful tool to assay the contribution of genetic variance to stress intolerance during prenatal or post-natal development. Here, KCNJ11 K ATP channel gene knockout↔wild-type chimeras were engineered through diploid aggregation. Integration of wild-type embryonic stem cells into zona pellucida-denuded morula derived from knockout embryos achieved varying degrees of incorporation of stress-tolerant tissue within the K ATP channel-deficient background. Despite the stress-vulnerable phenotype of the knockout, ex vivo derived mosaic blastocysts tolerated intrauterine transfer and implantation, followed by full-term embryonic development in pseudopregnant surrogates to produce live chimeric offspring. The development of adult chimerism from the knockout↔wild-type mosaic embryo offers thereby a new paradigm to probe the ecogenetic control of the K ATP channel-dependent stress response.

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