PT  - JOURNAL ARTICLE
AU  - Dengpiao Xie
AU  - Juan Wang
AU  - Gaizun Hu
AU  - Chaoling Chen
AU  - Hu Yang
AU  - Joseph K. Ritter
AU  - Yun Qu
AU  - Ningjun Li
TI  - Kidney-targeted delivery of PHD2 siRNA with nanoparticles alleviated renal ischemia/reperfusion injury
AID  - 10.1124/jpet.121.000667
DP  - 2021 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - JPET-AR-2021-000667
4099  - http://jpet.aspetjournals.org/content/early/2021/06/08/jpet.121.000667.short
4100  - http://jpet.aspetjournals.org/content/early/2021/06/08/jpet.121.000667.full
AB  - Background: Inhibition of HIF-prolyl hydroxylase (PHD) has been shown to protect against various kidney diseases. However, there are controversial reports on the effect of PHD inhibition in renoprotection. The present study determined whether delivery of PHD2 siRNA using a siRNA carrier, folic acid (FA)-decorated polyamidoamine dendrimer generation 5 (G5-FA), would mainly target kidneys and protect against renal ischemia/reperfusion injury (I/R). Methods: The renal I/R was generated by clipping the renal pedicle for 30 minutes in uninephrectomized mice. Mice were sacrificed 48 hours after I/R. Normal saline or G5-FA complexed with control or PHD2 siRNA was injected via tail vein 24 h before ischemia. Results: After the injection of near-infrared fluorescent dye-labeled G5-FA, the fluorescence was mainly detected in kidneys, but not in other organs. The reduction of PHD2 mRNA and protein was only observed in kidneys but not in other organs after injection of PHD2-siRNA- G5-FA complex. The injection of PHD2-siRNA-G5-FA significantly alleviated renal I/R injury, as shown by the inhibition of increases in serum creatinine and BUN, the blockade of increases in KIM-1 and NGAL and the improvement of histological damage compared with mice treated with control siRNA. Conclusion: PHD2 siRNA can be delivered specifically into kidneys using G5-FA and that local knockdown of PHD2 gene expression within the kidney alleviates renal I/R injury. Therefore, G5-FA is an efficient siRNA carrier to deliver siRNA into the kidney, and that local inhibition of PHD2 within the kidney may be a potential strategy for the management of acute I/R injury. Significance Statement Folic acid (FA)-decorated polyamidoamine dendrimer generation 5 (G5-FA) was demonstrated to be an effective carrier to deliver siRNA into kidneys. Delivery of PHD2 siRNA with G5-FA effectively protected the kidneys against the acute renal ischemia/reperfusion injury.