TY - JOUR
T1 - The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats
AU - Hiragushi, Keita
AU - Wada, Jun
AU - Eguchi, Jun
AU - Matsuoka, Takashi
AU - Yasuhara, Akihiro
AU - Hashimoto, Izumi
AU - Yamashita, Tetsuji
AU - Hida, Kazuyuki
AU - Nakamura, Yoshio
AU - Shikata, Kenichi
AU - Minamino, Naoto
AU - Kangawa, Kenji
AU - Makino, Hirofumi
N1 - Funding Information:
This work was supported by Uehara Memorial Foundation, The Naito Foundation, ONO Medical Foundation, Grant-in-Aid for Scientific Research (C), Ministry of Education, Science and Culture, Japan (14571025) to J. Wada and Grant-in-Aid for Scientific Research (B), Ministry of Education, Science and Culture, Japan (14370319) to H. Makino.
PY - 2004/2
Y1 - 2004/2
N2 - Background. Since adrenomedullin (AM) elicits vasodilatation by binding to specific AM receptors consisted of calcitonin-receptor-like receptor (CRLR)/receptor-activity-modifying protein 2 (RAMP2) or CRLR/receptor-activity- modifying protein 3 (RAMP3) on endothelial cells and stimulating nitric oxide production, AM possibly involves in glomerular capillary dilatation in early phase of diabetic nephropathy. Methods. Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats at 4 weeks after the injection were employed for expression studies of AM, RAPM2, and RAMP3. The measurement of AM peptide levels in kidney tissue, plasma, and urine was performed. Human aortic endothelial cells (HAEC) were used to investigate functional link between glucose-induced AM production and nitric oxide release. Results. STZ rats showed glomerular hypertrophy and increased urinary NO2- and NO3- excretion. By Northern blot analyses, AM and RAPM2 mRNAs significantly increased in the kidneys of STZ rats, while RAMP3 mRNA was not altered. In STZ rats, AM peptide was actively secreted into urine (1280 ± 360 fmol/day vs. control 110 ± 36 fmol/day). AM peptide was mainly detected on cortical and medullary collecting duct cells in control rat kidneys and AM peptide and mRNA were up-regulated on afferent arterioles and glomeruli of STZ rats. RAMP2 expression was detected on afferent arterioles and not in glomeruli in control rats and it was up-regulated on glomerular endothelial cells in STZ rats. In HAEC culture, D-glucose stimulated AM and nitric oxide production and they were suppressed by addition of AM antisense oligodeoxynucleotides. Conclusion. Up-regulated expression of AM and RAMP2 in afferent arterioles and glomeruli may be related to selective dilatation of glomerular capillary in acute phase of type 1 diabetes.
AB - Background. Since adrenomedullin (AM) elicits vasodilatation by binding to specific AM receptors consisted of calcitonin-receptor-like receptor (CRLR)/receptor-activity-modifying protein 2 (RAMP2) or CRLR/receptor-activity- modifying protein 3 (RAMP3) on endothelial cells and stimulating nitric oxide production, AM possibly involves in glomerular capillary dilatation in early phase of diabetic nephropathy. Methods. Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats at 4 weeks after the injection were employed for expression studies of AM, RAPM2, and RAMP3. The measurement of AM peptide levels in kidney tissue, plasma, and urine was performed. Human aortic endothelial cells (HAEC) were used to investigate functional link between glucose-induced AM production and nitric oxide release. Results. STZ rats showed glomerular hypertrophy and increased urinary NO2- and NO3- excretion. By Northern blot analyses, AM and RAPM2 mRNAs significantly increased in the kidneys of STZ rats, while RAMP3 mRNA was not altered. In STZ rats, AM peptide was actively secreted into urine (1280 ± 360 fmol/day vs. control 110 ± 36 fmol/day). AM peptide was mainly detected on cortical and medullary collecting duct cells in control rat kidneys and AM peptide and mRNA were up-regulated on afferent arterioles and glomeruli of STZ rats. RAMP2 expression was detected on afferent arterioles and not in glomeruli in control rats and it was up-regulated on glomerular endothelial cells in STZ rats. In HAEC culture, D-glucose stimulated AM and nitric oxide production and they were suppressed by addition of AM antisense oligodeoxynucleotides. Conclusion. Up-regulated expression of AM and RAMP2 in afferent arterioles and glomeruli may be related to selective dilatation of glomerular capillary in acute phase of type 1 diabetes.
KW - Adrenomedullin
KW - Endothelial cell nitric oxide synthase (ecNOS)
KW - Glomerular hypertrophy
KW - Hyperfiltration
KW - Nitric oxide
KW - Vasodilatation
UR - http://www.scopus.com/inward/record.url?scp=1642520797&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1642520797&partnerID=8YFLogxK
U2 - 10.1111/j.1523-1755.2004.00407.x
DO - 10.1111/j.1523-1755.2004.00407.x
M3 - Article
C2 - 14717924
AN - SCOPUS:1642520797
SN - 0085-2538
VL - 65
SP - 540
EP - 550
JO - Kidney International
JF - Kidney International
IS - 2
ER -
