AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease.
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AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease. / Fraune, Christoph; Lange, Sascha; Krebs, Christian; Hölzel, Alexandra; Baucke, Jana; Divac, Nevena; Schwedhelm, Edzard; Streichert, Thomas; Velden, Joachim; Garrelds, Ingrid M; Danser, A H Jan; Frenay, Anne-Roos; van Goor, Harry; Jankowski, Vera; Stahl, Rolf A.K.; Nguyen, Genevieve; Wenzel, Ulrich.
In: AM J PHYSIOL-RENAL, Vol. 303, No. 7, 7, 10.2012, p. 1037-1048.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease.
AU - Fraune, Christoph
AU - Lange, Sascha
AU - Krebs, Christian
AU - Hölzel, Alexandra
AU - Baucke, Jana
AU - Divac, Nevena
AU - Schwedhelm, Edzard
AU - Streichert, Thomas
AU - Velden, Joachim
AU - Garrelds, Ingrid M
AU - Danser, A H Jan
AU - Frenay, Anne-Roos
AU - van Goor, Harry
AU - Jankowski, Vera
AU - Stahl, Rolf A.K.
AU - Nguyen, Genevieve
AU - Wenzel, Ulrich
PY - 2012/10
Y1 - 2012/10
N2 - 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.
AB - 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.
KW - Animals
KW - Male
KW - Treatment Outcome
KW - Mice
KW - Dose-Response Relationship, Drug
KW - Blood Pressure/drug effects
KW - Gene Expression/drug effects
KW - Albuminuria/drug therapy/metabolism/physiopathology
KW - Amides/pharmacology/therapeutic use
KW - Angiotensin II/metabolism
KW - Angiotensin II Type 1 Receptor Blockers/pharmacology/therapeutic use
KW - Fumarates/pharmacology/therapeutic use
KW - Kidney/drug effects/metabolism
KW - Losartan/pharmacology/therapeutic use
KW - Renal Insufficiency, Chronic/drug therapy/metabolism/physiopathology
KW - Renin/antagonists & inhibitors/metabolism
KW - Renin-Angiotensin System/drug effects
KW - Animals
KW - Male
KW - Treatment Outcome
KW - Mice
KW - Dose-Response Relationship, Drug
KW - Blood Pressure/drug effects
KW - Gene Expression/drug effects
KW - Albuminuria/drug therapy/metabolism/physiopathology
KW - Amides/pharmacology/therapeutic use
KW - Angiotensin II/metabolism
KW - Angiotensin II Type 1 Receptor Blockers/pharmacology/therapeutic use
KW - Fumarates/pharmacology/therapeutic use
KW - Kidney/drug effects/metabolism
KW - Losartan/pharmacology/therapeutic use
KW - Renal Insufficiency, Chronic/drug therapy/metabolism/physiopathology
KW - Renin/antagonists & inhibitors/metabolism
KW - Renin-Angiotensin System/drug effects
U2 - 10.1152/ajprenal.00672.2011
DO - 10.1152/ajprenal.00672.2011
M3 - SCORING: Journal article
C2 - 22791343
VL - 303
SP - 1037
EP - 1048
JO - AM J PHYSIOL-RENAL
JF - AM J PHYSIOL-RENAL
SN - 1931-857X
IS - 7
M1 - 7
ER -
