Renoprotective effect of chronic adrenomedullin infusion in Dahl salt-sensitive rats.
The present study was designed to examine whether chronic adrenomedullin infusion has renoprotective effects in hypertensive renal failure and the mechanism by which chronic adrenomedullin infusion exerts its effects. Dahl salt-sensitive rats and Dahl salt-resistant rats were fed a high salt diet starting at 6 weeks of age. Recombinant human adrenomedullin or vehicle was infused for 7 weeks in 11-week-old Dahl salt-sensitive rats. Dahl salt-resistant rat was used as a control. After 7 weeks, untreated Dahl salt-sensitive rats were characterized by decreased kidney function, abnormal morphological findings, increased hormone levels, increased renal tissue angiotensin II levels, and altered mRNA expressions of transforming growth factor beta (TGF-beta) and components of the renin-angiotensin system compared with Dahl salt-resistant rats. Chronic adrenomedullin treatment significantly improved renal function (serum creatinine -87%, creatinine clearance +114%, urinary protein excretion -59%) and histological findings (glomerular injury score -54%) without changing mean arterial pressure compared with untreated Dahl salt-sensitive rats. Interestingly, long-term human adrenomedullin infusion decreased the endogenous rat adrenomedullin level (-97%) with a slight increase of human adrenomedullin level. Chronic adrenomedullin treatment also significantly inhibited the increase of plasma renin concentration (-269%), aldosterone level (-82%), and renal tissue angiotensin II levels (-60%). Furthermore, adrenomedullin infusion significantly decreased the increases of mRNA expressions of TGF-beta (- 63%), angiotensin-converting enzyme (-137%), renin (-230%), and angiotensinogen (-38%) in renal cortex. These results suggest that increased endogenous adrenomedullin plays a compensatory role in chronic hypertensive renal failure and that long-term adrenomedullin infusion has renoprotective effects in this type of hypertension model, partly via inhibition of the circulating and renal renin-angiotensin system.
Nishikimi
Toshio
T
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. nishikim@dokkyomed.ac.jp
Mori
Yosuke
Y
Kobayashi
Naohiko
N
Tadokoro
Kazuyoshi
K
Wang
Xin
X
Akimoto
Kazumi
K
Yoshihara
Fumiki
F
Kangawa
Kenji
K
Matsuoka
Hiroaki
H
D053607:Adrenomedullin; D000804:Angiotensin II / Q000032:analysis; D000818:Animals; D003404:Creatinine / Q000097:blood / Q000652:urine; D004343:Drug Implants; D005921:Glomerulonephritis / Q000473:pathology / Q000517:prevention & control; D006728:Hormones / Q000097:blood; D006973:Hypertension / Q000150:complications; D007668:Kidney / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use*; D011507:Proteinuria / Q000517:prevention & control; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020303:Rats, Inbred Dahl; D051437:Renal Insufficiency / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012084:Renin-Angiotensin System / Q000187:drug effects; D012965:Sodium Chloride / Q000008:administration & dosage; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics
D004343:Drug Implants; D006728:Hormones; D010455:Peptides; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D053607:Adrenomedullin; D012965:Sodium Chloride; D003404:Creatinine