Key result
Combination therapy with losartan and doxercalciferol (0.4 and 0.6 microg/kg) for 20 weeks effectively prevented albuminuria and reduced glomerulosclerosis in diabetic mice.
Why the study?
Does doxercalciferol combined with losartan prevent albuminuria and glomerulosclerosis in a mouse model of diabetic nephropathy?
Does doxercalciferol combined with losartan prevent albuminuria and glomerulosclerosis in a mouse model of diabetic nephropathy?
Combination therapy with doxercalciferol and losartan synergistically prevents albuminuria and glomerulosclerosis in a mouse model of diabetic nephropathy by blocking compensatory renin upregulation.
No immediate clinical implications from mouse data; leaves open translation of combination benefits to human diabetic nephropathy.
The intrarenal renin-angiotensin system (RAS) plays a key role in the development of diabetic nephropathy. Recently, we showed that combination therapy with an AT(1) receptor blocker (ARB) and an activated vitamin D analog produced excellent synergistic effects against diabetic nephropathy, as a result of blockade of the ARB-induced compensatory renin increase. Given the diversity of vitamin D analogs, here we used a pro-drug vitamin D analog, doxercalciferol (1alpha-hydroxyvitamin D(2)), to further test the efficacy of the combination strategy in long-term treatment. Streptozotocin-induced diabetic DBA/2J mice were treated with vehicle, losartan, doxercalciferol (0.4 and 0.6 microg/kg), or losartan and doxercalciferol combinations for 20 wk. Vehicle-treated diabetic mice developed progressive albuminuria and glomerulosclerosis. Losartan alone moderately ameliorated kidney injury, with renin being drastically upregulated. A similar therapeutic effect was seen with doxercalciferol alone, which markedly suppressed renin and angiotensinogen expression. The losartan and doxercalciferol combination most effectively prevented albuminuria, restored glomerular filtration barrier structure, and dramatically reduced glomerulosclerosis in a dose-dependent manner. These effects were accompanied by blockade of intrarenal renin upregulation and ANG II accumulation. These data demonstrate an excellent therapeutic potential for doxercalciferol in diabetic renal disease and confirm the concept that blockade of the compensatory renin increase enhances the efficacy of RAS inhibition and produces synergistic therapeutic effects in combination therapy.
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Zhang et al. (2009) studied diabetic nephropathy. losartan and doxercalciferol combination vs. vehicle, losartan alone, or doxercalciferol alone was evaluated on albuminuria and glomerulosclerosis. Combination therapy with losartan and doxercalciferol (0.4 and 0.6 microg/kg) for 20 weeks effectively prevented albuminuria and reduced glomerulosclerosis in diabetic mice.
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