Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
Kidney Int. 2010 Jun;77(11):1000-9. doi: 10.1038/ki.2010.22. Epub 2010 Feb 24.
We recently showed that losartan and paricalcitol are synergistic in the treatment of diabetic nephropathy in a model of type 1 diabetes. To test this strategy in a model of type 2 diabetes, we treated 2-month-old diabetic Lprdb/db mice with losartan, paricalcitol, or a combination of losartan and paricalcitol for 3 months. Vehicle-treated diabetic mice developed progressive albuminuria and glomerular abnormalities with mesangial expansion and glomerulosclerosis compared to their non-diabetic littermate control mice. Accompanying damage of the glomerular filtration barrier was a marked reduction in podocyte number as well as reduced expression of slit diaphragm proteins. Further, there was increased glomerular expression of extracellular matrix proteins, monocyte chemoattractant protein-1 and transforming growth factor-beta. Losartan or paricalcitol each alone moderately ameliorated albuminuria and glomerular damage. However, their combined use showed a dramatic therapeutic synergism, manifested by prevention of progressive albuminuria, restoration of the glomerular filtration barrier, reversal of the decline in slit diaphragm proteins, reduced synthesis of extracellular matrix proteins, and reduction of glomerulosclerosis. These effects were accompanied by blockade of the compensatory increase of renin production and angiotensin I/II accumulation in the kidney. Thus, our study further shows that vitamin D analogs can increase the efficacy of AT1 receptor blockade, leading to a more effective prevention of kidney disease in type 2 diabetes.
我们最近表明，在 1 型糖尿病模型中，氯沙坦和帕立骨化醇在治疗糖尿病肾病方面具有协同作用。为了在 2 型糖尿病模型中测试这一策略，我们用氯沙坦、帕立骨化醇或氯沙坦和帕立骨化醇联合治疗 2 个月大的 1 型糖尿病 Lprdb/db 小鼠 3 个月。与非糖尿病同窝对照小鼠相比， vehicle 治疗的糖尿病小鼠出现进行性白蛋白尿和肾小球异常，伴有系膜扩张和肾小球硬化。伴随肾小球滤过屏障的损伤，足细胞数量明显减少，裂孔隔膜蛋白的表达减少。此外，肾小球外基质蛋白、单核细胞趋化蛋白-1 和转化生长因子-β的表达增加。氯沙坦或帕立骨化醇单独使用均可适度改善白蛋白尿和肾小球损伤。然而，它们的联合使用显示出显著的治疗协同作用，表现为阻止进行性白蛋白尿、恢复肾小球滤过屏障、逆转裂孔隔膜蛋白的下降、减少细胞外基质蛋白的合成以及减少肾小球硬化。这些作用伴随着肾素产生和血管紧张素 I/II 积累的代偿性增加的阻断。因此，我们的研究进一步表明，维生素 D 类似物可以增加 AT1 受体阻断的疗效，从而更有效地预防 2 型糖尿病中的肾脏疾病。
