AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease.
The role of the renin-angiotensin system in chronic kidney disease involves multiple peptides and receptors. Exerting antipodal pathophysiological mechanisms, renin inhibition and AT(1) antagonism ameliorate renal damage. However, it is unclear which mechanism exerts better nephroprotection. We compared the renin inhibitor aliskiren with the AT(1) antagonist losartan in mice with chronic kidney disease due to renal ablation. Doses were adjusted to equipotent inhibition of the renin-angiotensin system, determined via a dose-response quantifying plasma and renal renin expression. Six-week treatment with either 500 mg/l drinking water losartan or 50 mg·kg(-1)·day(-1) aliskiren significantly decreased albuminuria, glomerular damage, and transcription rates of renal injury markers to a similar extent. An array analysis comparing renal gene expression of losartan- and aliskiren-treated mice evaluating >34,000 transcripts demonstrated regulation for 14 genes only, with small differences. No superior nephroprotection was found by combining losartan and aliskiren. Compared with plasma concentrations, aliskiren accumulated ∼7- to 29-fold in the heart, liver, lung, and spleen and ∼156-fold in the kidney. After withdrawal, plasma concentrations dropped to zero within 24 h, whereas renal tissue concentrations declined slowly over days. Withdrawal of aliskiren in mice with chronic kidney disease revealed a significantly delayed re-increase in albuminuria compared with withdrawal of losartan. This study demonstrates equieffective nephroprotection of renin inhibition and AT(1) antagonism in mice with chronic kidney disease without additional benefit of combination therapy. These observations underscore the pivotal role of targeting ANG II to reduce renal injury.
Div. of Nephrology, Dept. of Medicine, Universitätsklinikum Hamburg-Eppendorf, Martinistraβe 52, 20246 Hamburg, Germany.
Christoph
C
Fraune
Sascha
S
Lange
Christian
C
Krebs
Alexandra
A
Hölzel
Jana
J
Baucke
Nevena
N
Divac
Edzard
E
Schwedhelm
Thomas
T
Streichert
Joachim
J
Velden
Ingrid M
IM
Garrelds
A H Jan
AH
Danser
Anne-Roos
AR
Frenay
Harry
H
van Goor
Vera
V
Jankowski
Rolf
R
Stahl
Genevieve
G
Nguyen
Ulrich Otto
UO
Wenzel
D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D016896:Treatment Outcome; D000092502:Renin Inhibitors
D000577:Amides; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D005650:Fumarates; D019808:Losartan; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren