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Antithrombin nanoparticles improve kidney reperfusion and protect kidney function
after ischemia-reperfusion injury
#MMPMID25651565
Chen J
; Vemuri C
; Palekar RU
; Gaut JP
; Goette M
; Hu L
; Cui G
; Zhang H
; Wickline SA
Am J Physiol Renal Physiol
2015[Apr]; 308
(7
): F765-73
PMID25651565
show ga
In the extension phase of acute kidney injury, microvascular thrombosis,
inflammation, vasoconstriction, and vascular endothelial cell dysfunction promote
progressive damage to renal parenchyma after reperfusion. In this study, we
hypothesized that direct targeting and pharmaceutical knockdown of activated
thrombin at the sites of injury with a selective nanoparticle (NP)-based thrombin
inhibitor, PPACK (phenylalanine-proline-arginine-chloromethylketone), would
improve kidney reperfusion and protect renal function after transient warm
ischemia in rodent models. Saline- or plain NP-treated animals were employed as
controls. In vivo 19F magnetic resonance imaging revealed that kidney
nonreperfusion was evident within 3 h after global kidney reperfusion at 34 ± 13%
area in the saline group and 43 ± 12% area in the plain NP group and
substantially reduced to 17 ± 4% (?50% decrease, P < 0.05) in the PPACK NP
pretreatment group. PPACK NP pretreatment prevented an increase in serum
creatinine concentration within 24 h after ischemia-reperfusion, reflecting
preserved renal function. Histologic analysis illustrated substantially reduced
intrarenal thrombin accumulation within 24 h after reperfusion for PPACK
NP-treated kidneys (0.11% ± 0.06%) compared with saline-treated kidneys (0.58 ±
0.37%). These results suggest a direct role for thrombin in the pathophysiology
of AKI and a nanomedicine-based preventative strategy for improving kidney
reperfusion after transient warm ischemia.
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