title: Renoprotective effect of chronic adrenomedullin infusion in Dahl salt-sensitive rats.
abstract: 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.
authors.affiliation: Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. nishikim@dokkyomed.ac.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikimi
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Mori
authors.forename: Naohiko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Tadokoro
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Kazumi
authors.initials: K
authors.lastname: Akimoto
authors.forename: Fumiki
authors.initials: F
authors.lastname: Yoshihara
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsuoka
mesh_terms: 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
chemical_list: 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