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Renal subcapsular infusion of siRNA as a novel method of gene silencing in the kidney

Transgenic and knockout technologies allowed the development of mouse lines for the functional analysis of genes on animal physiology. Classic gene knockout requires the deletion of a gene in ES cells and may result in embryonic lethality. Functional characterization in viable offspring may be confounded by the development of compensatory changes in utero. Innovative conditional knockouts allow the reversible gene silencing in a limited number of tissues; however, this technology is tedious and expensive, and is not always successful. As a viable alternative to these techniques, we tested the feasibility of using gene‐specific siRNA infused via an osmotic minipump into the subcapsular space of the kidney of uninephrectomized C57Bl/6J and BALB/cJ mice. A 7‐day siRNA infusion ensured optimum gene silencing without gross or histological changes in the renal parenchyma or spill over into other organ systems. At least 60% knockdown efficiency was observed for several genes tested, e.g., Snx1, DJ‐1, Pon2, Drd2, and Usp48, which are genes that regulate blood pressure (BP). These were accompanied by changes in systolic BP (ΔSBP=26±3 mm Hg for Snx1; 24±4, DJ‐1; 41±5, Pon2; 20±5, Drd2; −21±2, Usp48 [n=3–4/group]). Our novel subcapsular siRNA infusion offers the advantage of restricted gene silencing in one kidney only and precludes unforeseen compensatory mechanisms that may develop in classical knockout models.