Effect of combination therapy with angiotensin receptor blocker and 1,25-dihydroxyvitamin D(3) in type 2 diabetic nephropathy in KK-A(y)/Ta mice.
BACKGROUND
Although angiotensin II type 1 receptor blockers (ARB) have beneficial effects in patients with diabetic nephropathy, they may induce a compensatory increase in renin. Renin exhibits profibrotic actions independent of angiotensin II, which is regulated by extracellular signal-regulated kinase 1 and 2 (ERK1/2). Calcitriol (1,25(OH)(2)D(3)) is a negative inhibitor of the renin-angiotensin system and the present study examined the effects of combination therapy with an ARB and 1,25(OH)(2)D(3) on diabetic nephropathy in KK-A(y)/Ta mice.


METHODS
KK-A(y)/Ta mice were divided into four groups: ARB group, 1,25(OH)(2)D(3) group, combination group, and control group. The urinary albumin/creatinine ratio (ACR) was measured and the renal expression of renin, p-ERK1/2 and TGF-β1 protein determined.


RESULTS
The levels of urinary ACR in the combination group were significantly lower than those in the ARB or control group. Renal expression of renin in the ARB group was significantly increased compared with the control group but was significantly decreased in both the 1,25(OH)(2)D(3) and combination group. Renal expression of p-ERK1/2 in the combination group was significantly decreased compared with the control or ARB group. Expression of TGF-β1 protein in the ARB and combination groups, especially the combination group, was significantly decreased compared with those in the control group.


CONCLUSIONS
These data suggest that the addition of 1,25(OH)(2)D(3) to therapy with ARB further reduced proteinuria by suppressing the compensatory increase in renin expression in type 2 diabetic nephropathy. These effects might relate to suppression of renin, ERK1/2 and TGF-β1 expression which may or may not depend on angiotensin II.
Department of Internal Medicine, Division of Nephrology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Ikko
I
Ohara
Mitsuo
M
Tanimoto
Tomohito
T
Gohda
Takahiko
T
Yamazaki
Shinji
S
Hagiwara
Maki
M
Murakoshi
Tatsuya
T
Aoki
Hitoe
H
Toyoda
Yuji
Y
Ishikawa
Kazuhiko
K
Funabiki
Satoshi
S
Horikoshi
Yasuhiko
Y
Tomino
D000419:Albuminuria / Q000652:urine; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D002117:Calcitriol / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000209:etiology / Q000652:urine; D004359:Drug Therapy, Combination; D015870:Gene Expression / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D016896:Treatment Outcome
D057911:Angiotensin Receptor Antagonists; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053773:Transforming Growth Factor beta1; D003404:Creatinine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D012083:Renin; D002117:Calcitriol