Abstract
DNase I is apoptotic endonuclease that promotes toxic acute kidney injury (AKI) by cisplatin. It is the most studied, the most abundant, and the most active endonuclease in mammalian tissues. However, the regulation of this enzyme is not understood. We found that AKI by cisplatin in mice is associated with the generation of truncated, alternatively‐spliced DNase I isoform that lacks exon 4. The isoform was named Δ4DNase I. Expression of Δ4DNase I was associated with low DNase I protein expression, low DNase and nuclear endonuclease activity in mouse organs. Since it is missing some DNA‐ and actin‐binding sites with the skipped exon, Δ4DNase I has decreased DNA‐degrading and actin‐binding activity. Overexpression of Δ4DNase I suppresses DNase I and some other endonucleases as measured using real‐time RT‐PCR, Western blotting and activity assays. Δ4DNase I overexpression also protects NRK‐52E cells from cisplatin injury in vitro, and, thus, seems to be important mechanism of DNase I regulation during cisplatin AKI. NIH R01DK078908 and VA Merit Review grants to AGB and SVS.
Published Version
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