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2016 ; 37
(11
): 1467-1480
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Renal-targeting triptolide-glucosamine conjugate exhibits lower toxicity and
superior efficacy in attenuation of ischemia/reperfusion renal injury in rats
#MMPMID27397544
Fu Y
; Lin Q
; Gong T
; Sun X
; Zhang ZR
Acta Pharmacol Sin
2016[Nov]; 37
(11
): 1467-1480
PMID27397544
show ga
AIM: We previously reported a novel triptolide (TP)-glucosamine conjugate (TPG)
that specifically accumulated in kidneys and protected renal function from acute
ischemia/reperfusion (I/R) injury in rats. In this study we further examined the
molecular mechanisms underlying the renoprotective action of TPG. METHODS: The
renal-targeting of TPG was investigated in a human proximal renal tubular
epithelial cell line (HK-2) by measuring cell uptake of TP or TPG. The effects of
TP or TPG on cell cycle distribution and apoptosis rate of HK-2 cells were
assessed, and the activities of caspase-3 and caspase-9 were also measured. SD
rats were subjected to bilateral renal ischemia by temporarily clamping both
renal pedicles. The rats were administered TP (4.17 ?mol·kg(-1)·d(-1), iv) or TPG
(4.17 ?mol·kg(-1)·d(-1), iv) for 3 d before the renal surgery. The kidneys were
harvested after 24 h of recovery from the surgery. The levels of oxidative
stress, proinflammatory cytokines, chemotactic cytokines and intracellular
adhesion molecules in kidneys were examined. RESULTS: The uptake of TPG in HK-2
cells was 2-3 times higher than that of TP at the concentrations tested.
Furthermore, TPG targeting the proximal tubules was mediated through interactions
with megalin receptors. TP (40-160 nmol/L) concentration-dependently increased
G(2)/M arrest, apoptosis and caspase-3/caspase-9 activity in HK-2 cells, whereas
the same concentrations of TPG did not show those features when compared with the
control group. In I/R-treated rats, TPG administration caused more robust
down-regulation of proinflammatory cytokines (TNF-?, IL-6, IL-1, TGF-?) and
chemotactic cytokines (MCP-1) in the kidneys compared with TP administration,
suggesting the inhibition of the proliferation and accumulation of lymphocytes.
And TPG administration also caused more prominent inhibition on the levels of
oxidative stress and intracellular adhesion molecules in the kidneys, compared
with TP administration. CONCLUSION: The renal-targeting TPG is more effective and
less toxic than TP, in amelioration of I/R-induced rat renal injury, which may
provide a new avenue for the treatment of acute kidney injury.