Department of Internal Medicine, Division of Nephrology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Nephron Exp Nephrol. 2011;117(4):e124-32. doi: 10.1159/000320284. Epub 2010 Oct 13.
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.
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.
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.
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.
血管紧张素 II 型 1 型受体阻滞剂（ARB）对糖尿病肾病患者有益，但可能会引起肾素的代偿性增加。肾素具有独立于血管紧张素 II 的促纤维化作用，而血管紧张素 II 受细胞外信号调节激酶 1 和 2（ERK1/2）调节。骨化三醇（1,25(OH)(2)D(3)）是肾素-血管紧张素系统的负抑制剂，本研究探讨了 ARB 和 1,25(OH)(2)D(3)联合治疗对 KK-A(y)/Ta 小鼠糖尿病肾病的影响。
KK-A(y)/Ta 小鼠分为四组：ARB 组、1,25(OH)(2)D(3)组、联合组和对照组。测量尿白蛋白/肌酐比值（ACR），并测定肾组织中肾素、p-ERK1/2 和 TGF-β1 蛋白的表达。
联合组的尿 ACR 水平明显低于 ARB 组或对照组。与对照组相比，ARB 组肾组织中肾素的表达明显增加，但在 1,25(OH)(2)D(3)和联合组中则明显降低。与对照组或 ARB 组相比，联合组肾组织中 p-ERK1/2 的表达明显降低。ARB 和联合组，尤其是联合组，肾组织中 TGF-β1 蛋白的表达明显低于对照组。
这些数据表明，在 ARB 治疗的基础上添加 1,25(OH)(2)D(3)可通过抑制 2 型糖尿病肾病中肾素表达的代偿性增加进一步减少蛋白尿。这些作用可能与抑制肾素、ERK1/2 和 TGF-β1 表达有关，而这种表达可能依赖于也可能不依赖于血管紧张素 II。
