IN-VIVO SUPPRESSION OF THE RENAL NA+ P-I COTRANSPORTER BY ANTISENSE OLIGONUCLEOTIDES/

A 20-mer phosphorothioate oligonucleotide (AS1) aas designed to hybrid ize to the message for the rat kidney sodium phosphate cotransporter N aPi-2 close to the translation initiation site. Single intravenous dos es of this oligonucleotide were given to rats maintained on a low phos phorus diet to increase NaPi-2 expression. At 3 days after oligonucleo tide infusion, rats receiving 2.5 mu mol of AS1 exhibited a reduction in renal NaPi-2 to cyclophilin mRNA ratio by 40% +/- 17%, and rats rec eiving 7.5 mu mol of AS1 exhibited a reduction in NaPi-2 to cyclophili n mRNA ratio by 46% +/- 21%. Reversed-sequence ASI was without effect. The higher dose of 7.5 mu mol of AS1 also reduced the rate of phospha te uptake into renal brush border membrane vesicles and the expression of NaPi-2 protein detected by Western blotting in these resides. Reve rsed sequence ASI was again without effect on these parameters. These results suggest that systemically infused oligonucleotides can exert a ntisense effects in the renal proximal tubule.