科研之友
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摘要
The vascular isoform of ATP-sensitive K+ (K-ATP) channels regulates blood flow to all organs. The K-ATP channel is strongly inhibited by reactive oxygen and carbonyl species produced in diabetic tissue inflammation. To address how such channel inhibition impacts vascular regulation as well as tissue viability, we performed studies in experimental diabetic mice. Strikingly, we found that knockout of the Kcnj8 encoding Kir6.1 subunit (Kcnj8-KO) caused mice to be fatally susceptible to diabetes. Organ perfusion studies suggested that the lack of this vascular K+ channel handicapped activity-dependent vasodilation, leading to hypoperfusion, tissue hypoxia, and multi-organ failure. Morphologically, Kcnj8-KO mice showed greater inflammatory cell infiltration, higher levels of expression of inflammation indicator proteins, more severe cell apoptosis, and worse tissue disruptions. These were observed in the kidney, liver, and heart under diabetic condition in parallel comparison to tissues from WT mice. Patch clamping and molecular studies showed that the K-ATP channel was S-glutathionylated in experimental diabetes contributing to the inhibition of channel activity as well as the reduced arterial responses to vasodilators. These results suggest that the vascular K-ATP channel is organ protective in diabetic condition, and since the channel is suppressed by diabetic oxidative stress, therapeutical interventions to the maintenance of functional K-ATP channels may help to lower or prevent diabetic organ dysfunction.
- 出版日期2015-12
- 单位哈尔滨医科大学
