Key result
Adding calcitriol to ARB reduces albuminuria and suppresses compensatory renin increases in diabetic mice.
Why the study?
Although ARBs have beneficial effects in diabetic nephropathy, they may induce a compensatory increase in renin with profibrotic actions independent of angiotensin II, which may be modulated by 1,25(OH)2D3.
Does combination therapy with an ARB and 1,25(OH)2D3 reduce proteinuria and suppress renin expression in a mouse model of type 2 diabetic nephropathy?
Does combination therapy with an ARB and 1,25(OH)2D3 reduce proteinuria and suppress renin expression in a mouse model of type 2 diabetic nephropathy?
The addition of calcitriol to an ARB further reduces proteinuria in diabetic nephropathy by suppressing the compensatory increase in renin expression.
Hypothesis-generating for calcitriol add-on to ARB in diabetic nephropathy; requires human trials before any practice consideration.
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.
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Ohara et al. (2010) studied Type 2 diabetic nephropathy. Combination therapy with an ARB and 1,25(OH)2D3 vs. ARB alone, 1,25(OH)2D3 alone, and control group was evaluated on Urinary albumin/creatinine ratio (ACR) and renal expression of renin, p-ERK1/2 and TGF-β1 protein. Combination therapy with an ARB and 1,25(OH)2D3 significantly reduced urinary ACR and suppressed the compensatory increase in renin expression compared to ARB alone or control in diabetic mice.
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