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Aya Takaki

Publications and source records attributed to Aya Takaki.

6 recordsLinked to original sources
PubMed2006

Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo: a possible link between stress and coronary vasospasm.

Vasospastic angina is induced by stress, for which cortisol secreted by activated hypothalamic/pituitary/adrenal axis may play an important role. However, direct evidence for this notion is still lacking. In this study, we examined whether sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses in pigs in vivo and, if so, whether Rho-kinase, which we found is a key molecule of coronary vasospasm, is involved. Oral administration of cortisol (20 mg/kg per day) increased its serum level to that seen in restraint stress in pigs. Thus, we examined coronary vasomotor responses in the following 4 groups: (1) control (without cortisol); (2) cortisol (20 mg/kg per day, p.o.) for 9 days; (3) cortisol plus RU38486 (a glucocorticoids receptor antagonist, 10 mg/kg per day, p.o.) for 9 days; and (4) cortisol for 9 days followed by 6-week withdrawal. Coronary angiography showed that intracoronary serotonin caused coronary hyperconstriction and reduction in coronary blood flow associated with ischemic ECG changes (coronary vasospasm) in only the cortisol group. All of these responses were abolished by hydroxyfasudil, a specific Rho-kinase inhibitor, in vivo. Organ chamber experiments demonstrated that serotonin concentration-dependently caused hypercontractions of coronary vascular smooth muscle associated with Rho-kinase activation (as evidenced by the enhanced phosphorylation of myosin binding subunit, a substrate of Rho-kinase) in only the cortisol group. All of these responses were again inhibited by hydroxyfasudil in vitro. These results indicate that sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses through Rho-kinase activation, suggesting the link between stress and coronary vasospasm.

Administration, Oral↗
PubMed2004

Long-term cadmium exposure accelerates age-related mitochondrial changes in renal epithelial cells.

Long-term cadmium exposure leads to mitochondrial dysfunction in the proximal tubular epithelial cells. Mitochondrial DNA deletion may contribute to the pathogenesis of cadmium-induced nephropathy. The aim of our study is to clarify the accumulation of mitochondrial DNA deletion and mitochondrial dysfunction in the renal cortex of rats injected three times/week with 1 ml of 1 mM CdCl2 or saline for 80 weeks. After 40-week cadmium injection, mitochondrial number diminished, and cadmium in the renal cortex reached a saturation level. At this time interval, nearly 30% of cadmium in the whole cell fraction was found in the mitochondria. Cytochrome c oxidase (COX) activity in the proximal tubular epithelial cells decreased after 40-week exposure of cadmium. Oxidized phosphatidylcholine (oxPC) started to accumulate in the cytochrome c-positive mitochondria in some tubular epithelial cells after 80-week exposure. After 40 weeks, accumulation of the 4834-bp deletion in mitochondrial DNA was evident in both control and cadmium-treated groups. However, the amount of accumulated mitochondrial DNA deletion tended to increase after 40-week exposure, and was significantly greater after 80 weeks of exposure, compared to the control. Our results indicate that long-term cadmium exposure in rats accelerates accumulation of 4834-bp mitochondrial DNA deletions and impairment of mitochondrial function associated with accumulation of oxidized product.

Adenosine Triphosphate↗
PubMed2004

Mechanisms of cell death induced by cadmium and arsenic.

Cadmium (Cd) and arsenic (As) are known toxic metals in humans. As trioxide (As(2)0(3)) has been recently used as a mitochondria-targeting drug in acute promyelocytic leukemia. In the present study, we examined the intracellular action of these metals using rat kidney tubular cells and cells tolerant to the metals. The cells were cultured with CdCl(2) (1-10 micro M) or As(2)O(3) (1-2.5 micro M). Cells tolerant to Cd and As (Cd-T and As-T, respectively) were defined as cells that survived at toxic concentrations of each metal. Both Cd and As induced cell toxicity in a dose-dependent fashion, which was accompanied by fragmented DNA and decreased mitochondrial membrane potential. Intracellular glutathione (GSH) increased with the increase of Cd and As concentration. In Cd-T and As-T cells, GSH levels were twice those observed in normal cells. When each metal-tolerant culture was exposed to the other different metal, i.e., As or Cd, the protective property was maintained. However, when buthionine sulfoximine (BSO) was added to the metal-tolerant cultures, apoptosis was restored in both Cd-T and As-T. Our results indicate that (1) although GSH is increased in NRK52E by the addition of Cd and As, mitochondria-mediated apoptosis can be still induced, (2) the protective property against metal-induced cytotoxicity is identical in Cd-T and As-T cultures, and (3) although GSH was higher in the metal-tolerant cell lines, depression of GSH by BSO induced apoptosis. We conclude that Cd- and As-induced apoptosis is mediated by an identical mechanism involving intracellular GSH reactive oxidation.

Animals↗
PubMed2004

Cadmium-induced nephropathy in rats is mediated by expression of senescence-associated beta-galactosidase and accumulation of mitochondrial DNA deletion.

Long-term exposure to cadmium (Cd) induces perturbation of kidney proximal tubular epithelial cells. Mitochondrial dysfunction in renal cortical cells may contribute to the pathogenesis of Cd-induced nephropathy. In this study, we examined the accumulation of mitochondrial DNA (mtDNA) with a large deletion and cellular senescence in the renal cortex. Wistar rats at 8 weeks of age were intraperitoneally injected with 1 mL of 1 mM CdCl(2) or saline, 3 times/week for 5, 20, 40, or 80 weeks. Mitochondrial Cd content in the renal cortex was quantified by atomic absorption analysis. Cytochrome c oxidase (CCO) and senescence-associated beta-galactosidase (SA-beta-gal) activity were determined in renal cortex by enzyme-histochemistry. mtDNA in total DNA extracted from the renal cortex was amplified by PCR, and mtDNA deletions, including 4,834-bp (nt8118-nt12937) deletion, were determined and semiquantified. After 40 weeks of Cd injection, Cd levels in the renal cortex reached a saturation level, and 30% of the level of the whole-cell fraction was found in the mitochondria. CCO activity in the renal cortex, which was predominantly found in proximal tubular cells, decreased after 40 weeks of Cd exposure. Expression of SA-beta-gal was detected primarily in the proximal tubular cells and significantly increased after 80 weeks of Cd exposure. After 40 weeks of study, accumulation of 4,834-bp deletion in mtDNA was evident in both groups of rats; however, the amount of the deletion was significantly greater in Cd-treated rats than in control rats. Our results indicate that long-term Cd exposure induced a post-regenerative state of proximal tubular cells, which accelerated accumulation of 4,834-bp mtDNA deletions in the renal cortex, suggesting that Cd may be a senescence acceleration factor for kidney proximal tubular epithelial cells, which results in Cd-induced nephropathy.

Animals↗
PubMed2003

Mitochondrial DNA deletion of proximal tubules is the result of itai-itai disease.

BACKGROUND: The pathogenesis of itai-itai disease continues to be controversial, although cadmium (Cd) poisoning which arises via polluted water and rice in Japan is likely involved. Until recently, however, a well-defined animal model for Cd intoxication was not available. An animal model for itai-itai disease was produced in rats by low-dose Cd treatment, intraperitoneally for a period of 70-80 weeks. Osteomalacia followed the renal damage. RESULTS: A gene deletion in the mitochondrial DNA was found in the mitochondria of the proximal tubule cells of rats with chronic Cd intoxication, as was shown by the increased smaller PCR product seen by gel electrophoresis in one DNA region, where ATPase and cytochrome oxidase genes are located. However, the PCR product was different from that seen with a gene deletion associated with aging: del4834bp. Renal damage from Cd intoxication initially caused mitochondrial dysfunction indicated by the disturbance in reabsorption in the proximal tubules and decreased amounts of ATP, ATPase, and cytochrome oxidase with gradually progressing tubular proteinuria, and, finally, chronic renal failure with tubulointerstitial damage throughout the renal cortex. These gave rise to osteomalacia, subsequently. CONCLUSION: We concluded that in Cd poisoning, a mitochondrial gene deletion in the mitochondria of the proximal tubule cells was the primary event for the pathogenesis of osteomalacia in itai-itai disease.

Absorption↗