Inhibition of
hypoxia-inducible factor-
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
small interfering RNA (
siRNA) using an
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). 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 hours before
ischemia. 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 blood
urea nitrogen, the blockade of increases in kidney injury molecule-1 and
neutrophil gelatinase-associated lipocalin, and the improvement of histologic damage compared with mice treated with control
siRNA. 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
small interfering RNA (
siRNA) into kidneys. Delivery of
prolyl hydroxylase domain protein 2
siRNA with G5-FA effectively protected the kidneys against the acute renal
ischemia/reperfusion injury.