title: Renoprotective effects of direct renin inhibition in glomerulonephritis.
abstract: The development of glomerulonephritis causes glomerular injury and renal dysfunction and is thought to increase renin release, thus activating the renin-angiotensin system (RAS). The aims of this study were to demonstrate activation of the intrarenal RAS and determine the effects of direct renin inhibition (DRI) on the progression of glomerulonephritis. Rats were treated with anti-Thy1.1 antibody with or without DRI, aliskiren (30 mg/kg/d). In the glomerulonephritic rats, protein, microalbumin excretion levels, urinary angiotensinogen excretion, glomerular expansion score and intrarenal transforming growth factor-β and plasminogen activator inhibitor-1 mRNA levels were augmented compared with control rats; however, hypertension was not observed in the glomerulonephritic rats, and aliskiren treatment did not modify their blood pressure. The increases in urinary protein (94.7 ± 13.0 mg/d) and microalbumin (7.52 ± 2.6 mg/d) excretion were reduced by aliskiren (43.6 ± 4.5 mg/d of protein and 2.57 ± 0.7 mg/d of microalbumin). Furthermore, the progression of glomerular expansion and elevation of intrarenal transforming growth factor-β and plasminogen activator inhibitor-1 levels were prevented by aliskiren. Importantly, aliskiren suppressed the augmentation of urinary angiotensinogen levels, the increased angiotensinogen expression in the kidneys and the increases in Ang II levels in renal medulla induced by the anti-Thy1.1 antibody. These results suggest that DRI with aliskiren prevents intrarenal RAS activation leading to mitigation of the development of glomerulonephritis. In addition, the renoprotective effects of DRI on glomerulonephritis occur in a blood pressure-independent manner. Accordingly, treatment with aliskiren may be an effective approach to treat glomerulonephritis and other intrarenal RAS-associated kidney diseases.
authors.affiliation: Department of Physiology and the Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Miyata
authors.forename: Ryousuke
authors.initials: R
authors.lastname: Satou
authors.forename: Daisuke
authors.initials: D
authors.lastname: Inui
authors.forename: Akemi
authors.initials: A
authors.lastname: Katsurada
authors.forename: Dale
authors.initials: D
authors.lastname: Seth
authors.forename: Allison
authors.initials: A
authors.lastname: Davis
authors.forename: Maki
authors.initials: M
authors.lastname: Urushihara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Mitchell
authors.forename: L Gabriel
authors.initials: LG
authors.lastname: Navar
mesh_terms: D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use*; D005921:Glomerulonephritis / Q000378:metabolism* / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D005650:Fumarates; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren