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siRNA stabilized for  in vivo  applications is filtered and reabsorbed in the renal proximal tubule (PT), reducing mRNA expression transiently. Prior siRNA efforts have successfully prevented upregulation of mRNA in response to injury. We proposed reducing constitutive gene and protein expression of  LRP2  (megalin) in order to understand its molecular regulation in mice. Using siRNA targeting mouse  LRP2  (si LRP2 ), reduction of  LRP2  mRNA expression was compared to scrambled siRNA (siSCR) in mouse PT cells. Mice received si LRP2  administration optimized for dose, administration site, carrier solution, administration frequency, and administration duration. Kidney cortex was collected upon sacrifice. Renal gene and protein expression were compared by qRT-PCR, immunoblot, and immunohistochemistry (IHC). Compared to siSCR, si LRP2  reduced mRNA expression in PT cells to 16.6% ± 0.6%. In mouse kidney cortex, si LRP2  reduced mRNA expression to 74.8 ± 6.3% 3 h and 70.1 ± 6.3% 6 h after administration. mRNA expression rebounded at 12 h (160.6 ± 11.2%). No megalin renal protein expression reduction was observed by immunoblot or IHC, even after serial twice daily dosing for 3.5 days. Megalin is a constitutively expressed protein. Although  LRP2  renal mRNA expression reduction was achieved, siRNA remains a costly and inefficient intervention to reduce  in vivo  megalin protein expression.

In Vivo siRNA Delivery and Rebound of Renal LRP2 in Mice