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Scientific Reports Nov 2023The gonadotropin-releasing hormone (GnRH) pulse and surge are considered to be generated by arcuate kisspeptin/neurokinin B/dynorphin A (KNDy) neurons and anteroventral...
The gonadotropin-releasing hormone (GnRH) pulse and surge are considered to be generated by arcuate kisspeptin/neurokinin B/dynorphin A (KNDy) neurons and anteroventral periventricular nucleus (AVPV) kisspeptin neurons, respectively, in female rodents. The majority of KNDy and AVPV kisspeptin neurons express κ-opioid receptors (KORs, encoded by Oprk1) in female rodents. Thus, this study aimed to investigate the effect of a conditional Oprk1-dependent Kiss1 deletion in kisspeptin neurons on the luteinizing hormone (LH) pulse/surge and fertility using Kiss1-floxed/Oprk1-Cre rats, in which Kiss1 was deleted in cells expressing or once expressed the Oprk1/Cre. The Kiss1-floxed/Oprk1-Cre female rats, with Kiss1 deleted in a majority of KNDy neurons, showed normal puberty while having a one-day longer estrous cycle and fewer pups than Kiss1-floxed controls. Notably, ovariectomized (OVX) Kiss1-floxed/Oprk1-Cre rats showed profound disruption of LH pulses in the presence of a diestrous level of estrogen but showed apparent LH pulses without estrogen treatment. Furthermore, Kiss1-floxed/Oprk1-Cre rats, with Kiss1 deleted in approximately half of AVPV kisspeptin neurons, showed a lower peak of the estrogen-induced LH surge than controls. These results suggest that arcuate and AVPV kisspeptin neurons expressing or having expressed Oprk1 have a role in maintaining normal GnRH pulse and surge generation, the normal length of the estrous cycle, and the normal offspring number in female rats.
Topics: Rats; Female; Animals; Kisspeptins; Luteinizing Hormone; Estrogens; Gonadotropin-Releasing Hormone; Neurokinin B; Dynorphins; Neurons; Arcuate Nucleus of Hypothalamus
PubMed: 37993510
DOI: 10.1038/s41598-023-47222-5 -
GeroScience Apr 2024The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of...
The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of CKD, characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and fibrosis. Kisspeptins and their receptor, KISS1R, exert a pivotal influence on kidney pathophysiology and modulate age-related pathologies across various organ systems. KISS1R agonists, including kisspeptin-13 (KP-13), hold promise as novel therapeutic agents within age-related biological processes and kidney-related disorders. Our investigation aimed to elucidate the impact of KP-13 on the trajectory of CKD and uremic cardiomyopathy. Male Wistar rats (300-350 g) were randomized into four groups: (I) sham-operated, (II) 5/6 nephrectomy-induced CKD, (III) CKD subjected to a low dose of KP-13 (intraperitoneal 13 µg/day), and (IV) CKD treated with a higher KP-13 dose (intraperitoneal 26 µg/day). Treatments were administered daily from week 3 for 10 days. After 13 weeks, KP-13 increased systemic blood pressure, accentuating diastolic dysfunction's echocardiographic indicators and intensifying CKD-associated markers such as serum urea levels, glomerular hypertrophy, and tubular dilation. Notably, KP-13 did not exacerbate circulatory uremic toxin levels, renal inflammation, or fibrosis markers. In contrast, the higher KP-13 dose correlated with reduced posterior and anterior wall thickness, coupled with diminished cardiomyocyte cross-sectional areas and concurrent elevation of inflammatory (Il6, Tnf), fibrosis (Col1), and apoptosis markers (Bax/Bcl2) relative to the CKD group. In summary, KP-13's influence on CKD and uremic cardiomyopathy encompassed heightened blood pressure and potentially activated inflammatory and apoptotic pathways in the left ventricle.
Topics: Humans; Rats; Animals; Male; Aged; Kisspeptins; Receptors, Kisspeptin-1; Rats, Wistar; Renal Insufficiency, Chronic; Cardiomyopathies; Hypertension; Fibrosis
PubMed: 37987885
DOI: 10.1007/s11357-023-01017-8 -
Reproductive Toxicology (Elmsford, N.Y.) Jan 2024The impact of pesticides on reproductive health has been increasingly recognized. β-cypermethrin (β-CYP) and emamectin benzoate (EMB) are commonly used with...
Combined exposure of beta-cypermethrin and emamectin benzoate interferes with the HPO axis through oxidative stress, causing an imbalance of hormone homeostasis in female rats.
The impact of pesticides on reproductive health has been increasingly recognized. β-cypermethrin (β-CYP) and emamectin benzoate (EMB) are commonly used with agricultural workers. There are few published studies on the effects of combined poisoning of these two pesticides on the reproductive system. This study investigated the toxic effects and mechanism of β-CYP and EMB on the reproductive system of female rats based on the hypothalamic-pituitary-ovarian (HPO) axis. The hypothalamic GnRH content tended to decrease, and Kiss-1 and GPR-54 mRNA and protein expression tended to increase in exposed rats. FSH content was elevated for the pituitary gland, and Kiss-1 and GPR-54 mRNA and protein expression were enhanced in all experimental groups compared with the control group. E content in rat ovaries and ERα mRNA and protein expression were reduced by β-CYP and EMB. Furthermore, there were interactive effects of β-CYP and EMB on FSH and E release, pituitary GPR-54 mRNA and protein, and ovarian ERα mRNA expression. To investigate causes of damage, oxidative damage indicators were tested and showed that exposure to β-CYP and EMB decreased GSH-Px and SOD activities in the HPO axis, increased MDA levels in the hypothalamus and ovary together with LDH activities in the HPO axis, with an interaction effect on GSH-Px and SOD activities in the hypothalamus and pituitary gland as well as on MDA in the ovary. The above results support the screening of sensitive molecular biomarkers and evaluation of the adverse effects of pesticide exposure in greenhouse operations on reproductive health.
Topics: Rats; Female; Animals; Ovary; Estrogen Receptor alpha; Kisspeptins; Gonadotropin-Releasing Hormone; Follicle Stimulating Hormone; Oxidative Stress; Pesticides; Homeostasis; RNA, Messenger; Superoxide Dismutase; Ivermectin; Pyrethrins
PubMed: 37984602
DOI: 10.1016/j.reprotox.2023.108502 -
Gene Feb 2024Understanding the pathophysiology of idiopathic central precocious puberty (ICPP) is essential, in view of its consequences on reproductive health and metabolic...
Understanding the pathophysiology of idiopathic central precocious puberty (ICPP) is essential, in view of its consequences on reproductive health and metabolic disorders in later life. Towards this, estimation of circulating levels of the neuropeptides, viz; Kisspeptin (Kp-10), Neurokinin B (NKB) and Neuropeptide Y (NPY), acting upstream to Gonadotropin-Releasing Hormone (GnRH), has shown promise. Insights can also be gained from functional studies on genetic variations implicated in ICPP. This study investigated the pathophysiology of ICPP in a girl by exploring the therapeutic relevance of the circulating levels of Kp-10, NKB, NPY and characterizing the nonsynonymous KISS1R variant, LH, that she harbours, in a homozygous condition. Plasma levels of Kp-10, NKB and NPY before and after GnRH analog (GnRHa) treatment, were determined by ELISA. It was observed that GnRHa treatment resulted in suppression of circulating levels of Kp-10, NKB and NPY. Further, the H variant in KISS1R was generated by site directed mutagenesis. Post transient transfection of either L or H KISS1R variant in CHO cells, receptor expression was ascertained by western blotting, indirect immunofluorescence and flow cytometry. Kp-10 stimulated signalling response was also determined by phospho-ERK and inositol phosphate production. Structure-function studies revealed that, although the receptor expression in H KISS1R was comparable to L KISS1R, there was an enhanced signalling response through this variant at high doses of Kp-10. Thus, elevated levels of Kp-10, acting through H KISS1R, contributed to the manifestation of ICPP, providing further evidence that dysregulation of Kp-10/KISS1R axis impacts the onset of puberty.
Topics: Animals; Cricetinae; Female; Humans; Cricetulus; Gonadotropin-Releasing Hormone; Kisspeptins; Neurokinin B; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1
PubMed: 37981083
DOI: 10.1016/j.gene.2023.148016 -
Endocrine Mar 2024We examined how the sex steroids influence the synthesis of gonadotropins.
OBJECTIVE
We examined how the sex steroids influence the synthesis of gonadotropins.
MATERIALS AND METHODS
The effects of sex steroids estradiol (E2), progesterone (P4), and dihydrotestosterone (DHT) in pituitary gonadotroph cell model (LβT2 cells) in vitro and ovary-intact rats in vivo were examined. The effects of sex steroids on Kiss1 gene expression in the hypothalamus were also examined in ovary-intact rats.
RESULTS
In LβT2 cells, E2 increased common glycoprotein alpha (Cga) and luteinizing hormone beta (Lhb) subunit promoter activity as well as their mRNA expression. Although gonadotropin subunit promoter activity was not modulated by P4, Cga and Lhb mRNA expression was increased by P4. DHT inhibited Cga and Lhb mRNA expression with a concomitant decrease in their promoter activity. During the 2-week administration of exogenous E2 to ovary-intact rats, the estrous cycle determined by vaginal smears was disrupted. P4 or DHT administration completely eliminated the estrous cycle. Protein expression of all three gonadotropin subunits within the pituitary gland was inhibited by E2 or P4 treatment in vivo; however, DHT reduced Cga expression but did not modulate Lhb or follicle-stimulating hormone beta subunit expression. E2 administration significantly repressed Kiss1 mRNA expression in a posterior hypothalamic region that included the arcuate nucleus. P4 and DHT did not modulate Kiss1 mRNA expression in this region. In contrast, P4 administration significantly inhibited Kiss1 mRNA expression in the anterior region of the hypothalamus that included the anteroventral periventricular nucleus. The expression of gonadotropin-releasing hormone (Gnrh) mRNA in the anterior hypothalamic region, where the preoptic area is located, appeared to be decreased by treatment with E2 and P4.
CONCLUSION
Our findings suggest that sex steroids have different effects in the hypothalamus and pituitary gland.
Topics: Rats; Female; Animals; Ovary; Kisspeptins; Hypothalamus; Gonadotropins, Pituitary; Gonadotropin-Releasing Hormone; Estradiol; RNA, Messenger; Dihydrotestosterone; Gene Expression
PubMed: 37966704
DOI: 10.1007/s12020-023-03596-0 -
Fish Physiology and Biochemistry Dec 2023In Heteropneustes fossilis, kisspeptins (Kiss) and nonapeptides (NPs; vasotocin, Vt; isotocin, Itb; Val8-isotocin, Ita) stimulate the hypothalamus-pituitary-gonadal...
Kisspeptin modulation of nonapeptide and cytochrome P450 aromatase mRNA expression in the brain and ovary of the catfish Heteropneustes fossilis: in vivo and in vitro studies.
In Heteropneustes fossilis, kisspeptins (Kiss) and nonapeptides (NPs; vasotocin, Vt; isotocin, Itb; Val8-isotocin, Ita) stimulate the hypothalamus-pituitary-gonadal (HPG) axis, and estrogen feedback modulates the expression of these systems. In this study, functional interactions among these regulatory systems were demonstrated in the brain and ovary at the mRNA expression level. Human KISS1 (hKISS1) and H. fossilis Kiss2 (HfKiss2) produced biphasic effects on brain and ovarian vt, itb and ita expression at 24 h post injection: low and median doses produced inhibition, no change or mild stimulation, and the highest dose consistently stimulated the mRNA levels. The Kiss peptides produced an upregulation of NP mRNA expression at 24 h incubation of brain and ovarian slices by increasing the concentration of hKISS1 and HfKiss2. The kiss peptides stimulated brain cyp19a1b and ovary cyp19a1a expression, both in vivo and in vitro. Peptide234, a Kiss1 receptor antagonist, inhibited basal mRNA expression of the NPs, cyp19a1b and cyp19a1a, which was prevented by the Kiss peptides, both in vivo and in vitro. In all the experiments, HfKiss2 was more effective than hKISS1 in modulating mRNA expression. The results suggest that the NP and E systems are functional targets of Kiss peptides and interact with each other.
Topics: Female; Humans; Animals; Ovary; Kisspeptins; Catfishes; Aromatase; Brain; RNA, Messenger
PubMed: 37966680
DOI: 10.1007/s10695-023-01270-w -
Acta Histochemica Dec 2023Kisspeptin (Kp-10) is a neuropeptide that binds to GPR54 receptors, exerting several functions mainly in the nervous and reproductive systems of the body. However, its...
Kisspeptin (Kp-10) is a neuropeptide that binds to GPR54 receptors, exerting several functions mainly in the nervous and reproductive systems of the body. However, its effects and mechanisms of action on the skeletal system remain poorly understood. This study evaluated the effects of different concentrations of Kp-10 on in vitro osteogenic differentiation of multipotent mesenchymal stromal cells (MSCs) extracted from the bone marrow (BM) of adult Wistar rats. Two-month-old female rats were euthanized to extract BM from long bones to obtain MSCs. Four experimental groups were established in vitro: a control and Kp-10 at concentrations of 0.01, 0.05 and, 0.1 µg/mL. After induction of osteogenic differentiation, cell viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyl tetrazolium bromide (MTT) assay, alkaline phosphatase activity, collagen synthesis, percentage of area covered by MSCs/field and mineralized nodules/field, and immunocytochemistry of the GPR54 receptor tests. Furthermore, evaluation of gene transcripts for type I collagen, Runx-2, Bmp-2, bone sialoprotein, osteocalcin and osteopontin was performed using real-time RT-qPCR. It was observed that MSCs expressed GPR54 receptor to which Kp-10 binds during osteogenic differentiation, promoting a negative effect on osteogenic differentiation. This effect was observed at all the Kp-10 concentrations in a concentration-dependent manner, characterized by a decrease in the activity of alkaline phosphatase, collagen synthesis, mineralized nodules, and decreased expression of gene transcripts for type I collagen, osteocalcin, osteopontin, and Runx-2. Thus, Kp-10 inhibits in vitro osteogenic differentiation of MSCs extracted from the BM of adult Wistar rats.
Topics: Animals; Female; Rats; Alkaline Phosphatase; Bone Marrow; Bone Marrow Cells; Cell Differentiation; Cells, Cultured; Collagen Type I; Kisspeptins; Mesenchymal Stem Cells; Osteocalcin; Osteogenesis; Osteopontin; Rats, Wistar
PubMed: 37948785
DOI: 10.1016/j.acthis.2023.152112 -
Endocrinology Nov 2023The mechanism by which arcuate kisspeptin (ARNKISS) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to drive...
The mechanism by which arcuate kisspeptin (ARNKISS) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to drive pulsatile hormone secretion remains unclear in females. In order to study spontaneous synchronization within the ARNKISS neuron network, acute brain slices were prepared from adult female Kiss1-GCaMP6 mice. Analysis of both spontaneous synchronizations and those driven by high frequency stimulation of individual ARNKISS neurons revealed that the network exhibits semi-random emergent excitation dependent upon glutamate signaling through AMPA receptors. No role for NMDA receptors was identified. In contrast to male mice, ongoing tachykinin receptor tone within the slice operated to promote spontaneous synchronizations in females. As previously observed in males, we found that ongoing dynorphin transmission in the slice did not contribute to synchronization events. These observations indicate that a very similar AMPA receptor-dependent mechanism underlies ARNKISS neuron synchronizations in the female mouse supporting the "glutamate two-transition" model for kisspeptin neuron synchronization. However, a potentially important sex difference appears to exist with a more prominent facilitatory role for tachykinin transmission in the female.
Topics: Mice; Female; Male; Animals; Kisspeptins; Dynorphins; Arcuate Nucleus of Hypothalamus; Neurokinin B; Brain; Neurons; Glutamates; Gonadotropin-Releasing Hormone
PubMed: 37936337
DOI: 10.1210/endocr/bqad167 -
Journal of Assisted Reproduction and... Jan 2024Kisspeptin is an emerging biomarker for the discrimination of viable pregnancy. The aim of the study is to determine whether serum kisspeptin can predict the...
PURPOSE
Kisspeptin is an emerging biomarker for the discrimination of viable pregnancy. The aim of the study is to determine whether serum kisspeptin can predict the first-trimester miscarriage and compare it with serum HCG in the prediction of the first-trimester miscarriage.
METHODS
This study is a prospective case-control design including 178 women who had experienced early miscarriage (n = 21) and viable single pregnancy (n = 157), following frozen-thawed embryo transfer (FET) from May to December 2019. Serum samples on 14 days, 21 days, and 28 days after FET were collected for kisspeptin and HCG detection.
TRIAL REGISTRATION NUMBER
NCT03940495.
RESULTS
On day 21 after FET, serum kisspeptin levels were significantly lower in the early miscarriage group [0.260 (0.185-0.375)] vs in the viable single-pregnancy group [0.370 (0.280-0.495)] (p = 0.005). Similar results were shown on day 28 after FET, the serum kisspeptin levels were significantly lower in the early miscarriage group [0.270 (0.200-0.330)] vs in the viable single pregnancy group [0.670 (0.455-1.235)] (p < 0.001). But on day 14 after FET, serum kisspeptin levels were comparable in the early miscarriage group [0.260 (0.210-0.325)] and in the viable single-pregnancy group [0.280 (0.215-0.340)] (p = 0.551). Serum kisspeptin levels on days 21 and 28 have a poor predictive value of miscarriage compared with serum HCG levels. [Day 21: AUC = 0.687 (kisspeptin) and 0.816 (HCG); Day 28: AUC = 0.896 (kisspeptin) and 0.909 (HCG)].
CONCLUSIONS
Serum kisspeptin on day 14 failed to discriminate between miscarriage and ongoing pregnancies, and days 21 and 28 had poor predictive values of miscarriage.
Topics: Pregnancy; Female; Humans; Abortion, Spontaneous; Pregnancy Trimester, First; Prospective Studies; Kisspeptins; Fertilization in Vitro; Pregnancy Rate; Retrospective Studies
PubMed: 37935913
DOI: 10.1007/s10815-023-02974-x -
Reproduction (Cambridge, England) Jan 2024The transcriptional profiles of Kiss1 neurons from the arcuate and the rostral periventricular region of the third ventricle of the hypothalamus have been directly...
IN BRIEF
The transcriptional profiles of Kiss1 neurons from the arcuate and the rostral periventricular region of the third ventricle of the hypothalamus have been directly compared in diestrous female mice. Differentially expressed genes provide molecular signatures for these two populations of Kiss1 neurons and insights into their physiology.
ABSTRACT
The neuropeptide kisspeptin is produced by Kiss1 neurons and is required for normal mammalian fertility. The two main populations of Kiss1 neurons are located in the arcuate (ARC) and the rostral periventricular area of the third ventricle (RP3V) of the hypothalamus. To define the molecular signature of these Kiss1 populations, transcriptomics profiling was performed using purified Kiss1 neurons from diestrous stage female mice. From a data set of 7026 genes, 332 differentially expressed transcripts were identified between the Kiss1ARC and Kiss1RP3V neurons. These data have uncovered novel transcripts and expanded the receptor expression, co-transmitter and transcription factor profiles of Kiss1 neurons. Validation by quantitative RT-PCR confirmed differential expression of Cartpt, Ddc, Gal, Gda, Npy2r, Penk, Rasp18, Rxfp3, Slc18a2, and Th in Kiss1RP3V neurons and Gpr83, Hctr2, Nhlh2, Nmn, Npr3, Nr4a2, Nr5a2, Olfm2, Tac2 and Tacr3 in Kiss1ARC neurons. Enriched pathways common to both Kiss1 populations included the NF-kB, mTor, endocannabinoid, GPCR, Wnt and oestrogen signalling while some pathways (e.g. cytomegalovirus infection, dopaminergic and serotonergic biosynthesis) were specific to Kiss1RP3V neurons. Our gene expression data set augments the existing data sets describing the transcriptional profiles of Kiss1 neuronal populations.
Topics: Animals; Female; Mice; Arcuate Nucleus of Hypothalamus; Basic Helix-Loop-Helix Transcription Factors; Hypothalamus; Kisspeptins; Neurons; Neuropeptides; Receptors, G-Protein-Coupled; Signal Transduction; Gene Expression Profiling
PubMed: 37934722
DOI: 10.1530/REP-23-0342