Early treatment with olmesartan prevents juxtamedullary glomerular podocyte injury and the onset of microalbuminuria in type 2 diabetic rats.
BACKGROUND
Studies were performed to determine if early treatment with an angiotensin II (Ang II) receptor blocker (ARB), olmesartan, prevents the onset of microalbuminuria by attenuating glomerular podocyte injury in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes mellitus.


METHODS
OLETF rats were treated with either a vehicle, olmesartan (10 mg/kg/day) or a combination of nonspecific vasodilators (hydralazine 15 mg/kg/day, hydrochlorothiazide 6 mg/kg/day, and reserpine 0.3 mg/kg/day; HHR) from the age of 7-25 weeks.


RESULTS
OLETF rats were hypertensive and had microalbuminuria from 9 weeks of age. At 15 weeks, OLETF rats had higher Ang II levels in the kidney, larger glomerular desmin-staining areas (an index of podocyte injury), and lower gene expression of nephrin in juxtamedullary glomeruli, than nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. At 25 weeks, OLETF rats showed overt albuminuria, and higher levels of Ang II in the kidney and larger glomerular desmin-staining areas in superficial and juxtamedullary glomeruli compared to LETO rats. Reductions in mRNA levels of nephrin were also observed in superficial and juxtamedullary glomeruli. Although olmesartan did not affect glucose metabolism, it decreased blood pressure and prevented the renal changes in OLETF rats. HHR treatment also reduced blood pressure, but did not affect the renal parameters.


CONCLUSIONS
This study demonstrated that podocyte injury occurs in juxtamedullary glomeruli prior to superficial glomeruli in type 2 diabetic rats with microalbuminuria. Early treatment with an ARB may prevent the onset of albuminuria through its protective effects on juxtamedullary glomerular podocytes.
Department of CardioRenal and CerebroVascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan. sofue@med.kagawa-u.ac.jp
Tadashi
T
Sofue
Hideyasu
H
Kiyomoto
Hiroyuki
H
Kobori
Maki
M
Urushihara
Yoko
Y
Nishijima
Kumiko
K
Kaifu
Taiga
T
Hara
Sachiko
S
Matsumoto
Atsuhiko
A
Ichimura
Hiroyuki
H
Ohsaki
Hirofumi
H
Hitomi
Hiroshi
H
Kawachi
Melvin R
MR
Hayden
Adam
A
Whaley-Connell
James R
JR
Sowers
Sadayoshi
S
Ito
Masakazu
M
Kohno
Akira
A
Nishiyama
D000419:Albuminuria / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004195:Disease Models, Animal; D006830:Hydralazine / Q000627:therapeutic use; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D007093:Imidazoles / Q000627:therapeutic use*; D007606:Juxtaglomerular Apparatus / Q000293:injuries* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D050199:Podocytes; D051381:Rats; D020334:Rats, Inbred OLETF; D012110:Reserpine / Q000627:therapeutic use; D013777:Tetrazoles / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001786:Blood Glucose; D007093:Imidazoles; D008565:Membrane Proteins; D013777:Tetrazoles; C113267:nephrin; D006852:Hydrochlorothiazide; D006830:Hydralazine; D012110:Reserpine; C437965:olmesartan