Reduction of albuminuria by angiotensin receptor blocker beyond blood pressure lowering: evaluation in megsin/receptor for advanced glycation end products/inducible nitric oxide synthase triple transgenic diabetic nephropathy mouse model.
OBJECTIVE
Antihypertensive agents inhibiting the renin-angiotensin system (RAS), such as angiotensin II type 1 receptor blockers (ARB), are now part of the standard treatment of patients with diabetic nephropathy, regardless of the presence of systemic hypertension. Whether ARB achieve better renoprotection than other RAS-independent antihypertensive drugs has been an issue of controversy. Several lines of large clinical studies provided better renoprotection of ARB. However, a recent meta-analysis argued against additional benefits of ARB beyond blood pressure. We generated a novel mouse model of diabetic nephropathy; that is, megsin/receptor for advanced glycation end products/inducible nitric oxide synthase triple transgenic mice. This model is normotensive but progressively develops severe diabetic nephropathy that resembles those observed in humans.


METHODS
In the present study, we tested whether olmesartan (ARB) achieves better renoprotection than amlodipine (calcium channel blocker). Drug treatment was initiated at the age of 6 weeks and lasted for 12 weeks.


RESULTS
This model develops significant glomerular lesions and albuminuria even at the age of 5 weeks. Despite equal blood pressure lowering, only olmesartan suppressed the progression of albuminuria. Neither olmesartan nor amlodipine modified histological lesions.


CONCLUSIONS
Proteinuria and its reduction are known to predict the progression of diabetic nephropathy. Our results support the additional benefit of ARB beyond blood pressure lowering.
Ohtomo
Shuichi
S
Institute of Medical Sciences, Tokai University, Kanagawa, Japan.
Ito
Masaki
M
Izuhara
Yuko
Y
Van Ypersele De Strihou
Charles
C
Miyata
Toshio
T
D000419:Albuminuria / Q000188:drug therapy*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D004195:Disease Models, Animal; D007093:Imidazoles / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000502:physiology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D015843:Serpins / Q000235:genetics / Q000502:physiology*; D013777:Tetrazoles / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C491938:Serpinb7 protein, mouse; D015843:Serpins; D013777:Tetrazoles; C437965:olmesartan; D052247:Nitric Oxide Synthase Type II