The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats.
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.


CONCLUSIONS
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.
Hiragushi
Keita
K
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Wada
Jun
J
Eguchi
Jun
J
Matsuoka
Takashi
T
Yasuhara
Akihiro
A
Hashimoto
Izumi
I
Yamashita
Tetsuji
T
Hida
Kazuyuki
K
Nakamura
Yoshio
Y
Shikata
Kenichi
K
Minamino
Naoto
N
Kangawa
Kenji
K
Makino
Hirofumi
H
D053607:Adrenomedullin; D000818:Animals; D001011:Aorta / Q000166:cytology; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D002478:Cells, Cultured; D016373:DNA, Antisense; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000166:cytology; D015870:Gene Expression; D006801:Humans; D006984:Hypertrophy; D047908:Intracellular Signaling Peptides and Proteins; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000652:urine; D010455:Peptides / Q000097:blood / Q000235:genetics* / Q000652:urine; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D016373:DNA, Antisense; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009566:Nitrates; D009573:Nitrites; D010455:Peptides; C545503:RAMP2 protein, human; C545504:RAMP3 protein, human; D012333:RNA, Messenger; C545509:Ramp2 protein, rat; C545510:Ramp3 protein, rat; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D053607:Adrenomedullin; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat