Beneficial effects of combination therapy with olmesartan and azelnidipine in murine polycystic kidneys.
BACKGROUND
Some reports have discussed the synergic effects of angiotensin II receptor blockers and calcium channel blockers on vascular injury or microalbuminuria. The present study examined the effects of combination treatment with olmesartan and azelnidipine on polycystic kidney disease in a mouse model (DBA/2-FG pcy mouse) and its mechanisms.


METHODS
The mice were divided into the following groups: combination treatment (n = 21), olmesartan treatment alone (n = 23), azelnidipine treatment alone (n = 29) or untreated (n = 26). Mean blood pressure and kidney weight were measured at 4 and 8 weeks after the treatment. Renal expression of angiotensin II, gp91, nitrotyrosine and endothelial NO synthase (eNOS) were examined by immunostaining. In addition, extracellular signal-regulated kinase activation was evaluated by Western blotting.


RESULTS
Olmesartan decreased the numbers of angiotensin II and gp91-positive cells, mainly macrophages, and cyst size at 4 weeks. However, only combination treatment suppressed cell infiltration, extracellular signal-regulated kinase activation and interstitial fibrosis with a significant change in the kidney weight/body weight ratio. The azelnidipine and combination treatment increased the numbers of interstitial eNOS-positive cells.


CONCLUSIONS
The combination treatment protects against cyst enlargement in polycystic kidney disease by suppressing interstitial inflammation, fibrosis and oxidative stress by upregulating eNOS expression during disease course.
Tanifuji
Chiaki
C
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Suzuki
Yusuke
Y
Geot
Wong Mu
WM
Horikoshi
Satoshi
S
Takahashi
Hisahide
H
Tomino
Yasuhiko
Y
D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D004095:Dihydropyridines / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D007093:Imidazoles / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000473:pathology; D013777:Tetrazoles / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D001383:Azetidinecarboxylic Acid; C437965:olmesartan; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; C061679:azelnidipine