| Co-Investigator(Kenkyū-buntansha) |
CHIBA Keiko Morioka Junior College Iwate Prefectural University, Associated Professor, 生活科学科, 助教授 (90197137)
HARA Masyuki St.Marinanna University School of Medicine, Assistant Professor, 医学部, 講師 (10198898)
KUJIRAOKA Touru St.Marinanna University School of Medicine, Assistant, 医学部, 助手 (40130992)
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| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
Mehtylmercury (MeHg) causes renal injury in addition to central and peripheral neuropathy. To clarify the mechanism of neuro- and nephrotoxicity by MeHg, we investigated the effect of this compound on intercellular communication through gap junction channels in cultured rat renal proximal tubular cells and neuroplastma cells (PC-12). After confluence, the proximal tubular cells expressed gap junctional communication, as assessed by fluorescent dye transfer. On the hand, precise dye-coupling could not confirm in PC-12 neuroblastoma cells. Twenty minutes after exposure of renal proximal tubular cells to 30 μM MeHg, gap junctional intercellular communication was markedly inhibited before appearance of cytotoxicity. When the medium containing MeHg was changed to MeHg-free medium, dye coupling recovered abruptly. However, the dye-coupling was abolished again 30 min after replacement with control medium, and the cells were damaged. Intracellular calcium concentration ([CaィイD12+ィエD1]ィイD2iィエD2
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), which modulates the function of gap junctions, significantly increased following exposure of the cells to 30 μM MeHg and returned to control level following replacement with MeHg-free medium. Nitric oxide (NO), an ubiquitous messenger molecule, has been revealed to modulate GJIC via stimulation of guanylate cyclase. NO products did not always increase when gap junction closure occurred. These results suggest that the inhibiting effect of MeHg on gap junctional intercellular communication is related to the change in [CaィイD12+ィエD1]ィイD2iィエD2.
Heme oxygenase-1 (HO-1) are responsible for production of carbon monoxide, which has function as second messenger as well as NO. We have examined the induction of heme oxygenase-1 (HO-1) mRNAs in maternal and fetal organs by arsenic exposure to the pregnant rat. The remarkable increase in HO-1 mRNA levels were observed in both maternal and fetal liver and kidney. However, the expression of HO-1 mRNA in brain was slightly increased. Inorganic arsenic caused induction of HO-1 in all organs, while organic arsenic was unable to induce them. As a first step in studying the mechanism of rat HO-1 induction by arsenic, we have estimated the site of a cis-acting element that is responsible for arsenic-mediated induction of rat HO-1 gene, using cadmium-responsive element (Cd-RE). However, it is not responsive to arsenic. It is therefore conceivable that an arsenic-responsive element (As-RE) of rat HO-1 gene may not be present in the 5'-flanking region and its result indicates that As-RE may be present in 3'-flanking region. Less
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