scholarly journals Beneficial Role of Erythrocyte Adenosine A2B Receptor–Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia

Circulation ◽  
2016 ◽  
Vol 134 (5) ◽  
pp. 405-421 ◽  
Author(s):  
Hong Liu ◽  
Yujin Zhang ◽  
Hongyu Wu ◽  
Angelo D’Alessandro ◽  
Gennady G. Yegutkin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
High Altitude ◽  
Altitude Hypoxia ◽  
Kinase Activation ◽  
Beneficial Role ◽  
Protein Kinase Activation ◽  
A2b Receptor ◽  
Amp Activated Protein Kinase ◽  
Adenosine A2b

scholarly journals AMP-activated protein kinase activation ameliorates eicosanoid dysregulation in high-fat-induced kidney disease in mice

2019 ◽  
Vol 60 (5) ◽  
pp. 937-952 ◽  
Author(s):  
Anne-Emilie Declèves ◽  
Anna V. Mathew ◽  
Aaron M. Armando ◽  
Xianlin Han ◽  
Edward A. Dennis ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kidney Disease ◽  
Ampk Activation ◽  
High Fat ◽  
Kinase Activation ◽  
Venous Circulation ◽  
Protein Kinase Activation ◽  
Anti Inflammatory ◽  
Amp Activated Protein Kinase

High-fat diet (HFD) causes renal lipotoxicity that is ameliorated with AMP-activated protein kinase (AMPK) activation. Although bioactive eicosanoids increase with HFD and are essential in regulation of renal disease, their role in the inflammatory response to HFD-induced kidney disease and their modulation by AMPK activation remain unexplored. In a mouse model, we explored the effects of HFD on eicosanoid synthesis and the role of AMPK activation in ameliorating these changes. We used targeted lipidomic profiling with quantitative MS to determine PUFA and eicosanoid content in kidneys, urine, and renal arterial and venous circulation. HFD increased phospholipase expression as well as the total and free pro-inflammatory arachidonic acid (AA) and anti-inflammatory DHA in kidneys. Consistent with the parent PUFA levels, the AA- and DHA-derived lipoxygenase (LOX), cytochrome P450, and nonenzymatic degradation (NE) metabolites increased in kidneys with HFD, while EPA-derived LOX and NE metabolites decreased. Conversely, treatment with 5-aminoimidazole-4-carboxamide-1-β-D-furanosyl 5′-monophosphate (AICAR), an AMPK activator, reduced the free AA and DHA content and the DHA-derived metabolites in kidney. Interestingly, kidney and circulating AA, AA metabolites, EPA-derived LOX, and NE metabolites are increased with HFD; whereas, DHA metabolites are increased in kidney in contrast to their decreased circulating levels with HFD. Together, these changes showcase HFD-induced pro- and anti-inflammatory eicosanoid dysregulation and highlight the role of AMPK in correcting HFD-induced dysregulated eicosanoid pathways.

Erythrocyte Adenosine A2B Receptor-Mediated AMP-Activated Protein Kinase Prevents Hypoxia-Induced Tissue Injury in High Altitude By Inducing 2,3-Bisphosphoglycerate

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2664-2664
Author(s):  
Hong Liu ◽  
Yujin Zhang ◽  
Anren Song ◽  
Harry Karmouty Quintana ◽  
Almut Grenz ◽  
...  
Keyword(s):  
Protein Kinase ◽  
High Altitude ◽  
Tissue Injury ◽  
A2b Receptor ◽  
Key Enzyme ◽  
Amp Activated Protein Kinase ◽  
Plasma Adenosine ◽  
Deficient Mice ◽  
Adenosine A2b ◽  
O2 Binding

Abstract To function effectively in O2 uptake, delivery and release, erythrocytes rely on sophisticated regulation of hemoglobin (Hb)-O2 affinity by allosteric modulators, especially 2,3-bisphophosphoglycerate (2,3-BPG). Earlier studies had shown that elevated erythrocyte 2,3-BPG level is correlated to increased availability of oxygen to tissues in high altitudes. However, nothing is known how 2,3-BPG is induced in high altitude. Recent study revealed that plasma adenosine is increased in patient and mice with sickle cell disease and elevated adenosine signaling via A2B receptor (ADORA2B) induces 2,3-BPG and thereby promotes deoxy-sickle hemoglobin and subsequent sickling. However, whether adenosine is induced and its effect in 2,3-BPG induction in high altitude are unknown. To address this question, we recruited 24 low-land volunteers and placed them in high altitude for different time points. Here we report that: 1) plasma adenosine, a molecule well known to be induced under hypoxia, is increased and its elevation is correlated to elevated erythrocyte 2,3-BPG levels and decreased Hb-O2 affinity; and 2) elevated plasma adenosine is correlated to increased circulating ecto-5’-nucleotidase (CD73), a key enzyme responsible for generation of extracellular adenosine. Similar to humans, increased circulating CD73 activity, plasma adenosine levels and erythrocyte 2,3-BPG and decreased Hb-O2 binding affinity were observed in wild type (WT) mice under hypoxia condition mimicking our human high altitude studies. Moreover, we found that hypoxia-induced increased plasma adenosine, erythrocyte 2,3-BPG and decreased Hb-O2 binding affinity were significantly attenuated in CD73-deficient mice (CD73-/-). As such, hypoxia-induced tissue injury and cell apoptosis were significantly elevated in CD73-/- mice compared to WT mice. Mechanistically, we provide both in vitro and in vivo genetic evidence that erythrocyte adenosine A2B receptor (ADORA2B) is essential for 2,3-BPG induction and subsequent O2 release. This finding led us to further discover that AMP-Activated Protein Kinase (AMPK) functions downstream of ADORA2B underlying adenosine-induced 2,3-BPG induction and O2 release by direct phosphorylation of 2,3-BPG mutase, a key enzyme for 2,3-BPG production. Finally, we demonstrated that treatment of metformin, a FDA approved potent AMPK agonist, induced erythrocyte 2,3-BPG levels and triggered O2 release and thereby prevented hypoxia-induced tissue injury in both CD73-/- mice and erythrocyte specific ADORA2B-deficient mice. Overall, our studies have revealed that erythrocyte ADORA2B-mediated AMPK activation is a novel mechanism underlying hypoxia-induced 2,3-BPG levels and thereby highlight its beneficial role to prevent hypoxia-induced tissue injury. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document