title: Elevated ecto-5'-nucleotidase-mediated increased renal adenosine signaling via A2B adenosine receptor contributes to chronic hypertension.
abstract: BACKGROUND
  Hypertension is the most prevalent life-threatening disease worldwide and is frequently associated with chronic kidney disease (CKD). However, the molecular basis underlying hypertensive CKD is not fully understood.
  
  
  OBJECTIVE
  We sought to identify specific factors and signaling pathways that contribute to hypertensive CKD and thereby exacerbate disease progression.
  
  
  RESULTS
  Using high-throughput quantitative reverse-transcription polymerase chain reaction profiling, we discovered that the expression level of 5'-ectonucleotidase (CD73), a key enzyme that produces extracellular adenosine, was significantly increased in the kidneys of angiotensin II-infused mice, an animal model of hypertensive nephropathy. Genetic and pharmacological studies in mice revealed that elevated CD73-mediated excess renal adenosine preferentially induced A2B adenosine receptor (ADORA2B) production and that enhanced kidney ADORA2B signaling contributes to angiotensin II-induced hypertension. Similarly, in humans, we found that CD73 and ADORA2B levels were significantly elevated in the kidneys of CKD patients compared with normal individuals and were further elevated in hypertensive CKD patients. These findings led us to further discover that elevated renal CD73 contributes to excess adenosine signaling via ADORA2B activation that directly stimulates endothelin-1 production in a hypoxia-inducible factor-α-dependent manner and underlies the pathogenesis of the disease. Finally, we revealed that hypoxia-inducible factor-α is an important factor responsible for angiotensin II-induced CD73 and ADORA2B expression at the transcriptional level.
  
  
  CONCLUSIONS
  Overall, our studies reveal that angiotensin II-induced renal CD73 promotes the production of renal adenosine that is a prominent driver of hypertensive CKD by enhanced ADORA2B signaling-mediated endothelin-1 induction in a hypoxia-inducible factor-α-dependent manner. The inhibition of excess adenosine-mediated ADORA2B signaling represents a novel therapeutic target for the disease.
authors.affiliation: Departments of Biochemistry and Molecular Biology,University of Texas Medical School at Houston, TX 77030, USA.
authors.forename: Weiru
authors.initials: W
authors.lastname: Zhang
authors.forename: Yujin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Dai
authors.forename: Chen
authors.initials: C
authors.lastname: Ning
authors.forename: Renna
authors.initials: R
authors.lastname: Luo
authors.forename: Kaiqi
authors.initials: K
authors.lastname: Sun
authors.forename: Louise
authors.initials: L
authors.lastname: Glover
authors.forename: Almut
authors.initials: A
authors.lastname: Grenz
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Zhang
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism; D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D006977:Hypertension, Renal / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D058851:GPI-Linked Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D043704:Receptor, Adenosine A2B; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D015720:5'-Nucleotidase; C548241:NT5E protein, human; C548242:Nt5e protein, mouse; D000241:Adenosine
keywords: adenosine; chronic renal disease; hypertension