| Project/Area Number |
11470217
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Research Institute for Production Development |
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Principal Investigator |
MUKOYAMA Masashi Research Inst.for Production Development, Researcher, 成人病科学研究室, 研究員 (40270558)
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| Co-Investigator(Kenkyū-buntansha) |
MARUYAMA Takayuki Ono Pharmaceutical Co.Research Institute, Researcher, 創薬第一研究所, 研究員
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1999: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | Prostaglandin / Prostanoid receptor / Diabetes mellitus / Diabetic nephropathy / Mesangium / Knockout mouse / Hypertension / Extracellular matrix |
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| Research Abstract |
Prostaglandins (PGs) and their receptors may be implicated in various renal disorders such as diabetic nephropathy and hypertension. To explore the roles of prostanoid receptors in the kidney, we studied their expression and functional significance in cultured mesangial cells as well as the effects of the pharmacological blockade using experimental disease models.
Cultured rat mesangial cells expressed EP_1 and EP_4 subtypes among four PGE_2 receptors. PGE_2 exhibited a biphasic effect on proliferation of mesangial cells showing a maximal stimulation at 〜10 nM, and cell growth was stimulated via the EP_1 receptor by Ca mobilization, whereas it was inhibited through the EP_4 receptor by cAMP stimulation. Mesangial cells cultured under high glucose conditions showed augmented cell growth, and such high glucose-induced mesangial proliferation was almost completely abolished by the addition of selective EP_1 antagonists. In this condition, PGE_2 production was increased while cAMP productio
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n via EP_4 was significantly attenuated, indicating that the imbalance between EP_1 and EP_4 signaling with relatively augmented autocrjne PGE_2/EP_1 system is important for the enhanced proliferation under high glucose conditions. Similarly, such imbalance with attenuated EP_4 while enhanced EP_1 signaling was present in mesangial cells from stroke-prone spontaneously hypertensive rats and may explain the basis for highly proliferative nature of these cells in culture.
To clarify a role of possible imbalance of prostanoid receptors in vivo, we next examined the effect of EP_1 blockade in a streptozotocin-induced diabetic nephropathy model in rats. Chronic oral administration of a selective EP_1 antagonist into diabetic rats effectively ameliorated the histological and functional impairment as well as proteinuria in diabetic rats. Furthermore, treatment with an EP_1 antagonist in spontaneously hypertensive rats resulted in the amelioration of hypertensive glomerular injuries.
These results indicate that the abnormalities in renal prostanoid receptors may underlie the pathophysiology of various renal disorders, suggesting that the pharmacological modulation of the renal prostanoid receptors with selective ligands may become a novel therapeutic strategy in renal diseases. Less
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