Hypercalcemia Leads to Delayed Corneal Wound Healing in Ovariectomized Rats

Nagai, Noriaki; Ogata, Fumihiko; Kawasaki, Naohito; Ito, Yoshimasa; Funakami, Yoshinori; Okamoto, Norio; Shimomura, Yoshikazu

doi:10.1248/bpb.b15-00227

Cited by 8 publications

(4 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This decrease may be caused by other hormones that regulate Ca 2+ levels in the body, such as calcitonin and parathyroid hormone, and these changes in the biological characteristics correspond to those seen in postmenopausal women. These results are similar to previous reports using OVX rats, 21) and show that the OVX rats used in this study were suitable for investigating changes in Ca 2+ levels and IL-18 expression in lenses after menopause.…”

Section: Resultssupporting

confidence: 92%

See 1 more Smart Citation

Increased Expression of Interleukin-18 in Lenses of Ovariectomized Rats

Nagai

Ogata

Kawasaki

et al. 2016

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

Previous studies showed an increased prevalence of cataracts in postmenopausal women. In this study, we investigated changes in the levels of calcium ion (Ca 2 ) and interleukin (IL)-18, which are factors in cataract development, in the lenses of ovariectomized (OVX) rats, a model of postmenopausal woman. Although the Ca 2 content in the blood of OVX rats increased 1 month after ovariectomy and subsequently decreased, the Ca 2 content in the lenses was unchanged in OVX rats 1-3 months after ovariectomy. The Ca 2 -ATPase activity in the lenses of OVX rats peaked 1 month after ovariectomy, and the behavior of Ca 2 -ATPase activity in lenses of OVX rats was similar to that of the Ca 2 concentration in the blood. It is possible that hypercalcemia increases the Ca 2 inflow into the lens; however, the enhanced Ca 2 -ATPase activity prevents the Ca 2 level from rising. On the other hand, we found that the levels of both IL-18 and interferon (IFN)-γ in the lenses of OVX rats were significantly increased as compared with the lenses of sham (control) rats during the period 1-3 months after surgery. These results suggest that the expression of IFN-γ via IL-18 in the lenses of OVX rats is induced by ovariectomy, and that excessive IL-18 and IFN-γ production in the lenses may be related to cataract development in postmenopausal women. These findings support those of previous studies that assessed lens opacification in postmenopausal women.Key words interleukin-18; lens; ovariectomized rat; interferon-γ; calcium Cataracts are defined as any alteration in the optical homogeneity of the lens or a decrease in its transparency. 1,2) Exposure to reactive oxygen species, interleukin (IL) or interferon (IFN)-γ induced by UV in sunlight are considered to result in a breakdown of lens homeostasis, resulting in an elevation in the calcium ion (Ca 2+ ) content of the lens. This elevated Ca 2+ content has been deduced to activate calpain, a Ca 2+ -dependent protease, leading to an increased degradation of lens proteins, such as crystallin proteins, resulting in an opaque lens.3,4) Therefore, the regulation of Ca 2+ levels in lens is important to prevent opacification. Previous studies have shown an increased prevalence of cataracts in postmenopausal women, and estrogen has been reported to be effective in preventing age-related cataracts. [5][6][7][8] Estrogen is a hormone that participates in regulating calcium (Ca) levels in the body, and postmenopausal women experience a drop in estrogen secretion. Bone resorption is regulated by estrogen, and a decrease in estrogen level leads to a decrease in vitamin D. Since vitamin D enhances Ca 2+ absorption from the small intestine, [9][10][11][12] postmenopausal women are at greater risk of osteoporosis and hypercalcemia/ hypocalcemia via the dysfunction in Ca 2+ regulation due to a chronic reduction in circulating estrogen levels.9-12) This reduced capacity to regulate Ca 2+ levels may be related to the onset of cataracts via an increase in Ca 2+ levels in the lens. Estrogens are also kno...

show abstract

Section: Resultssupporting

confidence: 92%

“…The OVX rat is an accepted female animal model to mimic postmenopausal women. 21,23) The OVX procedure promotes bone loss. Following bilateral ovariectomy, serum Ca 2+ levels rise and bone mass decreases due to the loss of estrogen.…”

mentioning

confidence: 99%

Increased Expression of Interleukin-18 in Lenses of Ovariectomized Rats

Nagai

Ogata

Kawasaki

et al. 2016

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

show abstract

“…The abrasion of the corneal epithelium in the normal and STZ rats was performed as described previously [ 41 , 55 , 70 , 71 , 72 , 73 ]. The rats were anesthetized with sodium pentobarbital (30 mg/kg, i.p.…”

Section: Methodsmentioning

confidence: 99%

A Proteomic Approach for Understanding the Mechanisms of Delayed Corneal Wound Healing in Diabetic Keratopathy Using Diabetic Model Rat

Yamamoto

Otake

Hiramatsu

et al. 2018

IJMS

Self Cite

View full text Add to dashboard Cite

Diabetes mellitus is a widespread metabolic disorder, and long-term hyperglycemia in diabetics leads to diabetic keratopathy. In the present study, we used a shotgun liquid chromatography/mass spectrometry-based global proteomic approach using the cornea of streptozotocin-induced diabetic (STZ) rats to examine the mechanisms of delayed corneal wound healing in diabetic keratopathy. Applying a label-free quantitation method based on spectral counting, we identified 188 proteins that showed expression changes of >2.0-fold in the cornea of STZ rats. In particular, the level of lumican expression in the cornea of STZ rats was higher than that of the normal rats. In the cornea of the normal rat, the expression level of lumican was elevated during the wound healing process, and it returned to the same expression level as before cornea injury after the wound was healed completely. On the other hand, a high expression level of lumican in the cornea of STZ rats was still maintained even after the wound was healed completely. In addition, adhesion deficiency in corneal basal cells and Bowman’s membrane was observed in the STZ rat. Thus, abnormally overexpressed lumican may lead to adhesion deficiency in the cornea of STZ rats.

show abstract

“…In addition, previous studies have revealed that an increased intracellular Ca 2+ concentration inhibits epithelial proliferation and promotes epidermal-like differentiation in the mouse cornea [8,10]. Furthermore, hypercalcemia appears to retard corneal wound healing in ovariectomized rats, while, using human corneal epithelial cells, an enhanced intracellular Ca 2+ level results in a decrease in cell viability [11]. These findings are consistent with the clinical observation that chelation of Ca 2+ by the topical application of ethylene-diamine-tetra-acetic acid (EDTA) is an effective way of treating band keratopathy [12,13].…”

Section: Introductionmentioning

confidence: 98%