2002 Fiscal Year Final Research Report Summary
A Study for Elucidation of Functional Mechanism of High Molecular Weight Substances in Urine on Calcium Oxalate Stone Formation
| Project/Area Number |
12307032
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Urology
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| Research Institution | Asahikawa Medical College |
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Principal Investigator |
YACHIKU Sunao Asahikawa Medical College, Dept. of Urology, Professor, 医学部, 教授 (60028579)
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| Co-Investigator(Kenkyū-buntansha) |
NODA Shinji Kurume Univ. School of Medicine, Dept. of Urology, Professor, 医学部, 教授 (90080853)
KOHRI Kenjiro Nagoya City Univ., Dept. of Urology, Professor, 医学部, 教授 (30122047)
KURITA Takashi Kinki Univ. School of Medicine, Dept. of Urology, Professor, 医学部, 教授 (10088528)
SUZUKI Koji Kanazawa Medical College, Dept. of Urology, Professor, 医学部, 教授 (70064615)
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| Project Period (FY) |
2000 – 2002
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| Keywords | Urolithiasis / Heparan sulfate / Osteopontin / Calcium oxalate stone / Prothrombin / Phosphatidylserine / Apoptosis / Macroarray |
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| Research Abstract |
1. Study of crystal-cell interactions: An experimental model of calcium oxalate (CaOx) stones, suitable for investigation of crystal-cell interactions, has been established. It was confirmed that the phosphatidylserine exposure on the outer leaflet of the cell membrane of renal collecting duct cells could be evaluated quantitatively by using this model. Increased phosphatidylserine expressing cells and activation of the caspase family (intracellular signal transduction systems for apoptosis) were noted with increasing urinary oxalate excretion and calcium oxalate crystals. 2. Purification of stone-related proteins and their molecular biological analysis: Osteopontin (OPN) and calprotectin were purified. The adhesion of CaOx crystals to MDCK cells was promoted by OPN, while it was suppressed by thrombin and antisense oligonucleotide. It seems likely that OPN-DNA polymorphism in patients with urinary tract stones is involved in mutation of the enhancer regions that are related to synthes
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is of OPN protein. 3. OPN antisense gene transfer: The introduction of OPN antisense gene to renal tubular cells suppressed OPN expression and CaOx stone formation in the kidneys. The addition of OPN and vitronectin to renal tubular cells in culture elevated the intracellular expression of OPN and promoted the phosphorylation of focal adhesion kinase. Catechin suppressed the formation of CaOx crystals through inhibiting apoptosis induced by oxidative stress. 4. Study of urinary tract stone inhibitors using antisense gene: Human syndecan-1-expressing renal tubular cells were established. Heparan sulfate (HS) and HS proteoglycan were found to suppress the cellular injury by oxalate exposure and the adhesion of CaOx crystals to the cell surface. It was suggested that HS prevented the cell injury by serving as a charge barrier that inhibited the influx of oxalate ions into the cells. 5. Effects to stone formation by controlling the expression of stone-related protein mRNA: Increased expression of renal prothrombin F-1 (RPTF-1) mRNA in rat kidneys with CaOx was confirmed. In the macro-array analysis, it was noted that RPTF-1 protein, OPN gene, and the multiple genes encoding inflammatory systems were increased after CaOx crystal exposure to the renal tubular cells. Less
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