title: Endothelin-1 contributes to  the progression of renal injury  in sickle cell disease via reactive  oxygen species.
abstract: OBJECTIVE
  Endothelin-1 (ET-1) is increased in patients with sickle cell disease and may contribute to the development of sickle cell nephropathy. The current study was designed to determine whether ET-1 acting via the ETA receptor contributes to renal injury in a mouse model of sickle cell disease.
  
  
  METHODS
  Adult, humanized HbSS (homozygous for sickle Hb) mice had increased ET-1 mRNA expression in both the cortex and the glomeruli compared with mice heterozygous for sickle and Hb A (HbAS controls). In the renal cortex, ETA receptor mRNA expression was also elevated in HbSS (sickle) mice although ETB receptor mRNA expression was unchanged. Ligand binding assays confirmed that sickle mice had increased ETA receptors in the renal vascular tissue when compared with control mice.
  
  
  RESULTS
  In response to PKC stimulation, reactive oxygen species production by isolated glomeruli from HbSS sickle mice was increased compared with that from HbSA controls, an effect that was prevented by 1 week in vivo treatment with the selective ETA antagonist, ABT-627. Protein and nephrin excretion were both elevated in sickle mice, effects that were also significantly attenuated by ABT-627. Finally, ETA receptor antagonism caused a significant reduction in mRNA expression of NADPH oxidase subunits, which may contribute to nephropathy in sickle cell disease.
  
  
  CONCLUSIONS
  These data support a novel role for ET-1 in the progression of sickle nephropathy, specifically via the ETA receptor, and suggest a potential role for ETA receptor antagonism in a treatment strategy.
authors.affiliation: 1epartment of Physiology, Augusta University, Augusta, GA 30912, USA.
authors.forename: J Brett
authors.initials: JB
authors.lastname: Heimlich
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Speed
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Connor
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Pollock
authors.forename: Tim M
authors.initials: TM
authors.lastname: Townes
authors.forename: Steffen E
authors.initials: SE
authors.lastname: Meiler
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.forename: David M
authors.initials: DM
authors.lastname: Pollock
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism*; D000755:Anemia, Sickle Cell / Q000150:complications / Q000378:metabolism*; D000818:Animals; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000819:agonists / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D017382:Reactive Oxygen Species; D044022:Receptor, Endothelin A