Effects of the Vitamin D Analog 2AMD in Cyclosporine-Induced Nephrotoxicity: Dose-Response and Antifibrotic Activity.

OBJECTIVES

In this study, we aimed to ascertain the efficacy and determine the dose effects of a new analog of vitamin D, 2α-methyl-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2AMD), in decreasing fibrosis and improving renal function in a rat model of kidney disease.

MATERIALS AND

METHODS

Using the cyclosporine model of chronic kidney disease, we tested 4 dose regimens (2.5, 5, 10, and 20 ng/kg) of 2AMD by subcutaneous administration. The 2AMD analog was compared with another analog, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD), given at 5 ng/kg.

RESULTS

After 28 days of cyclosporine administration with 5 ng/kg 2AMD or 2MD, blood urea nitrogen levels were decreased by 20% and 30%, with no increase in serum calcium. This dose significantly decreased collagen levels by 50%, as determined by relative measurements of birefringence elicited under polarized light following picrosirius red staining of kidney tissues. The 20 ng/kg dose of 2AMD was hypercalcemic, with consequent deleterious effects on measured parameters; however, all doses of 2AMD tested decreased collagen as determined by picrosirius staining. In Western blot analysis of extracts from rat kidneys treated with cyclosporine and 5 ng/kg 2AMD, the fibrotic markers, fibronectin and vimentin, were decreased compared with animals treated only with cyclosporine.

CONCLUSIONS

We found that both vitamin D analogs are potent inhibitors of kidney fibrosis with potential renoprotective activity.