title: Renin inhibition ameliorates renal damage through prominent suppression of both angiotensin I and II in human renin angiotensinogen transgenic mice with high salt loading.
abstract: BACKGROUND
  The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression. Aliskiren, a direct renin inhibitor, inhibits the rate-limiting step of the RAAS without any alternative pathway. It is proven to reduce albuminuria in CKD patients treated with angiotensin blockade. However, there are few reports which evaluate the advantage of aliskiren as the first-line drug against CKD progression in RAAS-activated hypertensive patients.
  
  
  METHODS
  Tsukuba hypertensive mice (THM), double transgenic mice carrying both the human renin and human angiotensinogen genes, were fed a high-salt diet and treated with hydraladine, ramipril and aliskiren for 10 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks during the experimental period. We evaluated renal histological changes and gene expression. Plasma angiotensin concentration was measured to evaluate the RAAS inhibitory effect.
  
  
  RESULTS
  High-salt-loaded THM showed severe hypertension and renal injury. All antihypertensive drugs suppressed blood pressure and prevented renal disease progression. RAAS blockade showed a higher renoprotective effect than hydraladine despite an equivalent blood pressure lowering effect. Aliskiren exhibited even stronger renoprotection than ramipril. Plasma angiotensin concentration was increased in THM fed both normal salt and high salt. Hydraladine did not alter the plasma angiotensin concentration. Ramipril significantly decreased angiotensin II concentration. Aliskiren treatment almost completely suppressed angiotensin I and resulted in lower angiotensin II concentration than ramipril treatment.
  
  
  CONCLUSIONS
  Aliskiren prevents renal disease progression by suppressing both angiotensin I and II in RAAS-activated pathology. Our data suggest the application of a renin inhibitor for preventing kidney disease progression in CKD patients.
authors.affiliation: Department of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan, yosidas-tky@umin.ac.jp.
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Yoshida
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishizawa
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ayuzawa
authors.forename: Kohei
authors.initials: K
authors.lastname: Ueda
authors.forename: Maki
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Wakako
authors.initials: W
authors.lastname: Kawarazaki
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Miki
authors.initials: M
authors.lastname: Nagase
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism; D000577:Amides / Q000494:pharmacology*; D000803:Angiotensin I / Q000097:blood*; D000804:Angiotensin II / Q000097:blood*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019610:Cytoprotection; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D017257:Ramipril / Q000494:pharmacology; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics; D017673:Sodium Chloride, Dietary; D013997:Time Factors; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000803:Angiotensin I; D000804:Angiotensin II; D000806:Angiotensin-Converting Enzyme Inhibitors; D000808:Angiotensinogen; D000959:Antihypertensive Agents; D005650:Fumarates; D006830:Hydralazine; D017257:Ramipril; D012083:Renin; D017673:Sodium Chloride, Dietary; D000092502:Renin Inhibitors; C534931:AGT protein, human; C446481:aliskiren