Estrogen‐dependent expression of the tissue kallikrein gene (<i>Klk1</i>) in the mouse uterus and its implications for endometrial tissue growth

Rajapakse, S.; Yamano, Noriko; Ogiwara, Katsueki; Hirata, Kyoji; Takahashi, Sumio; Takahashi, Takayuki

doi:10.1002/mrd.20567

Cited by 16 publications

(16 citation statements)

References 49 publications

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“…The serine protease cluster includes kallikrein 1 and several related peptidases, all of which were downregulated in estrus relative to proestrus (Supplemental Table S20B). Kallikrein 1 is downregulated in estrus relative to diestrus [6] and is increased by estrogen treatment [31]. Consistent with this, kallikrein 1 was upregulated in proestrus, i.e., when estrogen levels are high.…”

Section: Genes Affecting Uterine Morphology Architecture and Tissuementioning

confidence: 61%

Changes in Mouse Uterine Transcriptome in Estrus and Proestrus1

Yip

Suvorov

Connerney

et al. 2013

Biology of Reproduction

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Changes in the CD-1 mouse uterine transcriptome during proestrus and estrus were investigated to help elucidate mechanisms of uterine tissue remodeling during the estrus cycle and their regulation by estrogen and progesterone in preparation of the uterus for pregnancy. Mice were staged beginning at 6 weeks of age, and uterine horns were harvested after monitoring two estrus cycles. Microarray analysis of whole uterine horn RNA identified 2428 genes differentially expressed in estrus compared to proestrus, indicating there is extensive remodeling of mouse uterus during the estrus cycle, affecting ~10% of all protein-encoding genes. Many (~50%) of these genes showed the same differential expression in independent analyses of isolated uterine lumenal epithelial cells. Changes in gene expression associated with structural alterations of the uterus included remodeling of the extracellular matrix, changes in cell keratins and adhesion molecules, activation of mitosis and changes in major histocompatibility complex class II (MHCII) presentation, complement and coagulation cascades, and cytochrome P450 expression. Signaling pathways regulated during the estrus cycle, involving ligand-gated channels, Wnt and hedgehog signaling, and transcription factors with poorly understood roles in reproductive tissues, included several genes and gene networks that have been implicated in pathological states. Many of the molecular pathways and biological functions represented by the genes differentially expressed from proestrus to estrus are also altered during the human menstrual cycle, although not necessarily at the corresponding phases of the cycle. These findings establish a baseline for further studies in the mouse model to dissect mechanisms involved in uterine tissue response to endocrine disruptors and the development of reproductive tract diseases.

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Section: Genes Affecting Uterine Morphology Architecture and Tissuementioning

confidence: 61%

Changes in Mouse Uterine Transcriptome in Estrus and Proestrus1

Yip

Suvorov

Connerney

et al. 2013

Biology of Reproduction

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“…It has been previously shown that Klk1 mRNA is expressed in the endometrial glands of humans and mice [15, 17]. Therefore, glandular epithelial cells may be the potential source of KLK production in the uterine tissues.…”

Section: Resultsmentioning

confidence: 99%

“…In males, KLK2 and KLK3 transcripts are regulated by androgens; and androgen responsive elements (ARE) are present in the promoters of both KLK2 and 3 [33]. Conversely, KLK1 expression in mouse and rat uteri is influenced by E 2 [17]; and an estrogen responsive element (ERE) is found in the Klk1 promoter [34]. In humans, KLK levels in cervical and vaginal fluid are positively correlated with pregnancy and are possibly regulated by female steroid hormones [13].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, KLK1 and KLK3 transcripts are expressed at the highest level in human endometrium when circulating estradiol (E 2 ) is elevated [14, 15]. In rodents, E 2 increases KLK expression in the uterus [16, 17]. These findings suggest that KLKs are expressed in the human and mouse reproductive tracts and that some of the KLKs in the uteri are regulated by E 2 .…”

Section: Introductionmentioning

confidence: 99%

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Crucial role of estrogen for the mammalian female in regulating semen coagulation and liquefaction in vivo

García

Gewiss

et al. 2017

PLoS Genet

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Semen liquefaction changes semen from a gel-like to watery consistency and is required for sperm to gain mobility and swim to the fertilization site in the Fallopian tubes. Kallikrein-related peptidases 3 (KLK3) and other kallikrein-related peptidases from male prostate glands are responsible for semen liquefaction by cleaving gel-forming proteins (semenogelin and collagen). In a physiological context, the liquefaction process occurs within the female reproductive tract. How seminal proteins interact with the female reproductive environment is still largely unexplored. We previously reported that conditional genetic ablation of Esr1 (estrogen receptor α) in the epithelial cells of the female reproductive tract (Wnt7a) causes female infertility, partly due to a drastic reduction in the number of motile sperm entering the oviduct. In this study, we found that post-ejaculated semen from fertile wild-type males was solidified and the sperm were entrapped in Wnt7aCre/+ ;Esr1 f/f uteri, compared to the watery semen (liquefied) found in Esr1 f/f controls. In addition, semenogelin and collagen were not degraded in Wnt7aCre/+ ;Esr1 f/f uteri. Amongst multiple gene families aberrantly expressed in the absence of epithelial ESR1, we have identified that a lack of Klks in the uterus is a potential cause for the liquefaction defect. Pharmacological inhibition of KLKs in the uterus replicated the phenotype observed in Wnt7aCre/+ ;Esr1 f/f uteri, suggesting that loss of uterine and seminal KLK function causes this liquefaction defect. In human cervical cell culture, expression of several KLKs and their inhibitors (SPINKs) was regulated by estrogen in an ESR1-dependent manner. Our study demonstrates that estrogen/ESR1 signaling in the female reproductive tract plays an indispensable role in normal semen liquefaction, providing fundamental evidence that exposure of post-ejaculated semen to the suboptimal microenvironment in the female reproductive tract leads to faulty liquefaction and subsequently causes a fertility defect. Author summarySemen liquefaction has been considered to be solely modulated by prostate-derived kallikrein-related peptidases (KLKs), especially KLK3 (or prostate specific antigen). However, our research demonstrated that female mice lacking estrogen receptor alpha (ERα) in the uterine epithelial cells had a drastic decrease in Klk transcripts and semen from fertile males fails to liquefy within the uteri of these females. Therefore, our results provide a novel aspect that, due to an interplay between semen and female reproductive tract secretions, the physiology of semen liquefaction is more complicated than previously assumed. This information will advance research on semen liquefaction in the female reproductive tract, an area that has never been explored, and could lead to the development of diagnostic tools for unexplained infertility cases and non-invasive contraception technologies.

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“…A previous study demonstrated that KLK1 is involved in the normal development of uterine endometrial tissues (49). Bradykinin released from the endothelium plays a critical role in the regulation of the human cardiovascular system.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome reveals the overexpression of a kallikrein gene cluster (KLK1/3/7/8/12) in the Tibetans with high altitude-associated polycythemia

Gesang

Zhang

et al. 2016

International Journal of Molecular Medicine

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High altitude-associated polycythemia (HAPC) is a very common disease. However, it the disease is still unmanageable and the related molecular mechanisms remain largely unclear. In the present study, we aimed to explore the molecular mechanisms responsible for the development of HAPC using transcriptome analysis. Transcriptome analysis was conducted in 3 pairs of gastric mucosa tissues from patients with HAPC and healthy residents at a similar altitude. Endoscopy and histopathological analyses were used to examine the injury to gastric tissues. Molecular remodeling was performed for the interaction between different KLK members and cholesterol. HAPC was found to lead to morphological changes and pathological damage to the gastric mucosa of patients. A total of 10,304 differentially expressed genes (DEGs) were identified. Among these genes, 4,941 DEGs were upregulated, while 5,363 DEGs were downregulated in the patients with HAPC (fold change ≥2, P<0.01 and FDR <0.01). In particular, the kallikrein gene cluster (KLK1/3/7/8/12) was upregulated >17-fold. All the members had high-score binding cholesterol, particularly for the polymers of KLK7. The kallikrein gene cluster (KLK1/3/7/8/12) is on chromosome 19q13.3–13.4. The elevated levels of KLK1, KLK3, KLK7, KLK8 and KLK12 may be closely associated with the hypertension, inflammation, obesity and other gastric injuries associated with polycythemia. The interaction of KLKs and cholesterol maybe play an important role in the development of hypertension. The findings of the present study revealed that HAPC induces gastric injury by upregulating the kallikrein gene cluster (KLK1/3/7/8/12), which can bind cholesterol and result in kallikrein hypertension. These findings provide some basic information for understanding the molecular mechanisms responsible for HAPC and HAPC-related diseases.

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Estrogen‐dependent expression of the tissue kallikrein gene (Klk1) in the mouse uterus and its implications for endometrial tissue growth

Cited by 16 publications

References 49 publications

Changes in Mouse Uterine Transcriptome in Estrus and Proestrus1

Changes in Mouse Uterine Transcriptome in Estrus and Proestrus1

Crucial role of estrogen for the mammalian female in regulating semen coagulation and liquefaction in vivo

Transcriptome reveals the overexpression of a kallikrein gene cluster (KLK1/3/7/8/12) in the Tibetans with high altitude-associated polycythemia

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