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2015 ; 99
(11
): 2274-84
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Stimulation of Dopamine D3 Receptor Attenuates Renal Ischemia-Reperfusion Injury
via Increased Linkage With G?12
#MMPMID25989500
Wang Z
; Guan W
; Han Y
; Ren H
; Tang X
; Zhang H
; Liu Y
; Fu J
; He D
; Asico LD
; Jose PA
; Zhou L
; Chen L
; Zeng C
Transplantation
2015[Nov]; 99
(11
): 2274-84
PMID25989500
show ga
BACKGROUND: Renal ischemia-reperfusion (I/R) injury causes renal tubular
necrosis, apoptosis, and inflammation leading to acute renal dysfunction. Recent
studies have revealed that deletion of G?12 mitigates the renal damage due to I/R
injury. Our previous study showed that activation of dopamine D3 receptor (D3R)
increased its linkage with G?12, and hampered G?12-mediated stimulation of renal
sodium transport. In the present study, we used an in-vivo rat model and an in
vitro study of the renal epithelial cell line (NRK52E) to investigate whether or
not an increased linkage between D3R and G?12 contributes to the protective
effect of D3R on renal I/R injury. METHODS: For in vivo studies, I/R injury was
induced in a rat renal unilateral clamping model. For in vitro studies,
hypoxia/reoxygenation and cold storage/rewarming injuries were performed in
NRK52E cells. PD128907, a D3R agonist, or vehicle, was administered 15 minutes
before clamping (or hypoxia) in both the in vivo or in vitro studies. RESULTS: In
the rat renal unilateral clamping model, pretreatment with PD128907 (0.2 mg/kg,
intravenous) protected against renal I/R injury and increased survival rate
during a long-term follow-up after 7 days. A decrease in the generation of
reactive oxygen species, apoptosis, and inflammation may be involved in the
D3R-mediated protection because pretreatment with PD128907 increased renal
glutathione and superoxide dismutase levels and decreased malondialdehyde levels
in the I/R group. The increase in cytokines (TNF-?, IL-1?, and IL-10) and
myeloperoxidase in I/R injured kidney was also prevented with a simultaneous
decrease in the apoptosis of the epithelial cells and expression of apoptosis
biomarkers in kidney harvested 1 day after I/R injury. The increase in the
coimmunoprecipitation between D3R and G?12 with D3R stimulation paralleled the
observed renal protection from I/R injury. Moreover, in vitro studies showed that
transient overexpression of G?12 in the NRK52E cells attenuated the protective
effect of PD128907 on hypoxia/reoxygenation injury. The protective effect of
PD128907 might be of significance to renal transplantation because cold
storage/rewarming induced injury increased lactate dehydrogenase release and
decreased cell viability in NRK52E cells. Conversely, in the presence of
PD128907, the increased lactate dehydrogenase release and decreased cell
viability were reversed. CONCLUSIONS: These results suggest that activation of
D3R, by decreasing G?12-induced renal damage, may exert a protective effect from
I/R injury.
|Acute Kidney Injury/metabolism/pathology/*prevention & control
[MESH]