| Project/Area Number |
13671160
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Endocrinology
|
|---|
| Research Institution | Jichi Medical School |
|---|
Principal Investigator |
ISHIKAWA San-e Jichi Medical School, Professor, Department of Medicine, 医学部, 教授 (70112620)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
NAGASAKA Shoichiro Jichi Medical School, Assistant Professor, Department of Medicine, 医学部, 講師 (00296112)
KUSAKA Ikuyo Jichi Medical School, Instructor, Department of Medicine, 医学部, 助手 (30285788)
SAITO Takako Jichi Medical School, Instructor, Department of Medicine, 医学部, 助手 (90296103)
|
|---|
| Project Period (FY) |
2001 – 2002
|
| Project Status |
Completed (Fiscal Year 2002)
|
| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2001: ¥1,900,000 (Direct Cost: ¥1,900,000)
|
|---|
| Keywords | Vasopressin / Aquaporin-2 / Hyponatremia / Transcription / SIADH / Osmolality / プロモーター活性 / 遺伝子発現 |
|---|
| Research Abstract |
We examined the alteration in aquaporin-2 (AQP-2) water channel in pathological state of arginine vasopressin (AVP)-dependent hyponatremia. First, SIADH model was prepared in Sprague-Dawley rats by giving liquid diet and subcutaneous infusion of dDAVP. Serum Na level was decreased to below 120 mmol/l in the experimental SIADH rats, and urinary osmolality remained as low as 800-900 mmol/kg, that was significantly lower than that of 3,000-3,200 mmol/kg in the control rats. Thus, urinary concentrating defect was found, which is called as AVP escape phenomenon. There were marked reduction in AVP receptor binding and AVP V_2 receptor mRNA expression, but they were not different between the two groups. The expression of AQP-2 mRNA in kidney was upregulated in the SIADH rats, and its expression was significantly attenuated as compared to that in the dDAVP-excess rats, which were given solid diet and subcutaneous infusion of dDAVP. Similar results were obtained with kidney AQP-2 protein expression and urinary excretion of AQP-2. These in vivo studies indicate that either extracellular volume expansion or hypoosmolality may directly inhibit kidney AQP-2 mRNA expression, resulting in AVP escape in SIADH. Following in vitro study was carried out to examine whether osmolality directly regulate transcription of 5'-flanking region of AQP-2. The AQP-2 promoter gene (-9.5 kb) was obtained, and its activity was determined by luciferase assay. Cyclic AMP responsive element (CRE) was present until -1.1 kb. Hypertonic pressure of 600 mmol/kg increased the luciferase activity by approximately 2-fold in the AQP-2 promoter (-9.5〜-1.1 kb). Further study determined two osmolality responsive sites in the AQP-2 promoter gene (-9.5〜-7.7 kb and -6.0〜-4.2 kb).
|
