Transport of phosphorothioate oligonucleotides in kidney: implications for molecular therapy.

Published

Journal Article

The systemic administration of phosphorothioated antisense oligonucleotides has been demonstrated to be an effective strategy for the control of gene expression. Because previous studies have suggested both hepatic and renal accumulation of systemically administered oligonucleotides, we explored whether the kidney might be a site of free DNA transport. [32P]-phosphorothioate oligonucleotides (20 mers) were excreted in urine but cleared at only 30% of glomerular filtration rate. Plasma clearance of the label was very rapid (t1/2 approximately 5 min) but the half life of labeled S-deoxynucleotide excreted in urine was much slower (28 min). Infused oligonucleotide appeared in urine with little degradation. By autoradiography of renal tissue, labeled antisense oligonucleotides appeared within Bowman's capsule and the proximal tubule lumen. DNA was detected in association with brush border membrane and within tubular epithelial cells. Brush border membrane preparations from rat kidney contained oligonucleotide binding proteins as determined by gel mobility shift and UV cross linking assays. Because renal epithelial cells efficiently take up phosphorothioate oligonucleotides without apparent degradation, the kidney appears to be an excellent target for site-directed antisense therapy, but may be a site of antisense toxicity as well.

Full Text

Duke Authors

Cited Authors

  • Rappaport, J; Hanss, B; Kopp, JB; Copeland, TD; Bruggeman, LA; Coffman, TM; Klotman, PE

Published Date

  • May 1995

Published In

Volume / Issue

  • 47 / 5

Start / End Page

  • 1462 - 1469

PubMed ID

  • 7637275

Pubmed Central ID

  • 7637275

International Standard Serial Number (ISSN)

  • 0085-2538

Digital Object Identifier (DOI)

  • 10.1038/ki.1995.205

Language

  • eng

Conference Location

  • United States