Gene analysis and molecular drug discovery of ADPKD

• Project/Area Number: 15591713
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Teikyo University
• Principal Investigator: HORIE Shigeo Teikyo Univ, Dept. of Urology. School of Medicine, Professor and Chairman, 医学部, 教授 (40190243)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: ADPKD / polycystin-1 / endothelin-1 / MAPK / PWV / vascular endothelial function / PKD1 / 脈波伝播速度 / E-cardherin / beta-catenin / caspase

Research Abstract

In the Pkd1^<-/-> kidney, the renal parenchyma of Pkd1^<-/-> had numerous cysts. The hearts of Pkd1^<-/-> had a double-outlet right ventricle (DORV) and ventricular septal defect (VSD). It is well known that DORV is observed in endothelin-l(ET-1) deficient mice. ET-1 regulate ERK activation. So, to investigate whether polycystin-1 would regulate the ET-1 pathway, mouse embryonic fibroblast (MEF) was stimulated with ET-1 and the phosphorylation of ERK was examined with gel shift assay. The phosphorylation was hardly admitted in Pkd1^<-/-> MEF compared with Pkd1^<+/+> and Pkd1^<+/-> MEF. Moreover, the high osmotic pressure stimulation is known to the stimulation that activates ERK excluding ET-1. When the activation of ERK in the high osmotic pressure stimulation was examined to examine whether it was the one ET-1 peculiar a previous result, the phosphorylation was hardly admitted in Pkd1^<-/-> MEF compared with Pkd1^<+/+> and Pkd1^<+/-> MEF. MAPK activates AP-1, and adjusts the gene expression such as c-MYC. Pkd1^<-/-> has been intentionally decreasing the appearance of c-MYC by heart compared with a wild type. These results suggested that polycystin-1 take part in Pkd1^<-/-> in the signal transmission of MAPK/ERK2.
Ankle Brachial Index (ABI) and Pulse Wave Velocity (PWV) were measured for 18 ADPKD patients. These data showed good reverse-correlation between PWV, ABI and Ccr (PWV : P=0.0006, ABI : P=0.0285). Moreover, renal volume intentionally correlated only to PWV (P=0.0364).
These data suggests that the relation to the progress of renal failure and vascular endothelial function, and the possibility of a molecular drug development was expected.

Research Products

• [Journal Article] Pkd1 regulates immortalized proliferation of renal tubular epithetlial cells through p53 induction and JNK activation. (2005)
  • Author(s): Nishio S, Hatano M, Nagata M, Horie S, Koike T, Tokuhisa T, Mochizuki T
  • Journal Title: J Clin Invest.
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Calcium channel blocker versus angiotensin II receptor blocker in autosomal dominant polycystic kidney disease. (2005)
  • Author(s): Nutahata K, Higashihara E, Horie S, et al.
  • Journal Title: Nephron Clin Pract 99(1)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation. (2005)
  • Author(s): Nishio S, Hatano M, Nagata M, Horie S, Koike T, Tokuhisa T, Mochizuki T.
  • Journal Title: J Clin Invest.
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Calcium channel blocker versus angiotensin II receptor blocker in autosomal dominant polycystic kidney disease. (2005)
  • Author(s): Nutahara K, Higashihara E, Horie S, et al.
  • Journal Title: Nephron Clin Pract. 99(1)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Evidence for the presence of angiogenin in human testis (2004)
  • Author(s): Koga K, Osuga Y, Yano T, Ikezuki Y, Yoshino O, Hirota Y, Hirata T, Horie S, Ayabe T, Tsutsumi O, Taketani Y
  • Journal Title: J Androl. 25(3) Pages: 369-374
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Detection of circulating MUC7-positive cells by reverse transcription-polymerase chain reaction in bladder cancer patients (2004)
  • Author(s): Kinuo M, Okegawa T, Horie S, Nutahara K, Higashihara E.
  • Journal Title: Int J Urol 11(1) Pages: 38-43
  • NAID: 10011986866
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Evidence for the presence of angiogenin in human testis. (2004)
  • Author(s): Koga K, Osuga Y, Yano T, Ikezuki Y, Yoshino O, Hirota Y, Hirata T, Horie S, Ayabe T, Tsutsumi O, Taketani Y.
  • Journal Title: J Androl. 25(3) Pages: 369-74
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Detection of circulating MUC7-positive cells by reverse transcription- Polymerase chain reaction in bladder cancer patients. (2004)
  • Author(s): Kinjo M, Okegawa T, Horie S, Nutahara K, Higashihara E.
  • Journal Title: Int J Urol. 11(1) Pages: 38-43
  • NAID: 10011986866
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Evidence for the presence of angiogenin in human testis. (2004)
  • Author(s): Koga K, Osuga Y, Yano T, Ikezuki Y, Yoshino O, Hirota Y, Hirata T, Horie S, AYabe T, Tsutsumi O, Taketani Y.
  • Journal Title: J Androl. 25(3) Pages: 369-374
• [Journal Article] Detection of circulating MUC7-positive cells by reverse transcription-polymerase chain reaction in bladder cancer patients. (2004)
  • Author(s): Kinjo M, Okegawa T, Horie S, Nutahara K, Higashihara E.
  • Journal Title: Int J Urol. 11(1) Pages: 38-43
  • NAID: 10011986866
• [Publications] Kinjo M, Okegawa T, Horie S, Nutahara K, Higashihara E: "Detection of circulating MUC7-positive cells by reverse transcription-polymerase chain reaction in bladder cancer patients"Int J Urol.. 11(1). 38-43 (2004)
• [Publications] Azuma H, Horie S, Muto S, Otsuki Y, Matsumoto K. et al.: "Selective cancer cell apoptosis induced by FTY720; evidence for a Bcl-dependent pathway and impairment in ERK activity"Anticancer Res.. 23(4). 3183-3193 (2003)
• [Publications] Okegawa T, Kinjo M, Horie S, Nutahara K, Higashihara E: "Detection of mucin 7 gene expression in exfoliated cells in urine from patients with bladder tumor"Urology.. 62(1). 182-186 (2003)
• [Publications] Azuma H, Takahara S, Horie S, Muto S, Otsuki Y, Katsuoka Y: "Induction of apoptosis in human bladder cancer cells in vitro and in vivo caused by FYT720 treatment"J Urol.. 169(6). 2372-2377 (2003)
• [Publications] Okegawa T, Kinjo M, Ohta M, Miura I, Horie S, et al.: "Predictors of prostate cancer in repeat prostatic biopsy in men with serum total prostate-specific antigen between 4.1 and 10 ng/mL"Int J Urol.. 10(4). 201-206 (2003)
• [Publications] Tambo M, Ohta M, Murata A, Okegawa T, Horie S et al.: "A case of post-traumatic high flow priapism"Nippon Hinyokika Gakkai Zasshi.. 94(5). 578-581 (2003)