title: ET-1 deletion from endothelial cells protects the kidney during the extension phase of ischemia/reperfusion injury.
abstract: BACKGROUND
  The prognosis of patients after acute kidney injury (AKI) is poor and treatment is limited. AKI is mainly caused by renal ischemia/reperfusion injury (IRI). During the extension phase of IRI, endothelial damage may participate in ischemia and inflammation. Endothelin-1 (ET-1) which is mostly secreted by endothelial cells is an important actor of IRI, particularly through its strong vasoconstrictive properties. We aimed to analyze the specific role of ET-1 from the endothelial cells in AKI.
  
  
  METHODS
  We used mice lacking ET-1 in the vascular endothelial cells (VEETKO). We induced IRI in VEETKO mice and wild type controls by clamping both kidneys for 30min. Sham operated mice were used as controls. Mice were sacrificed one day after IRI in order to investigate the extension phase of IRI. Kidney function was assessed based on serum creatinine concentration. Levels of expression of ET-1, its receptor ET(A), protein kinase C, eNOS, E-Cadherin and inflammation markers were evaluated by real time PCR or western blot. Tubular injury was scored on periodic acid Schiff stained kidney preparations. Lumen and wall area of small intrarenal arteries were measured on kidney slices stained for alpha smooth muscle cell actin. Oxidative stress, macrophage infiltration and cell proliferation was evaluated on slices stained for 8-hydroxy-2'-deoxyguanosine, F4/80 and PCNA, respectively.
  
  
  RESULTS
  IRI induced kidney failure and increased ET-1 and ET(A) receptor expression. This was accompanied by tubular injury, wall thickening and reduction of lumen area/wall area ratio of small renal arteries, increased oxidative stress and inflammation. These parameters were attenuated in VEETKO mice.
  
  
  CONCLUSIONS
  Our results suggest that suppression of ET-1 from the endothelial cells attenuates IRI kidney injury. Blocking ET-1 effects may represent a therapeutic strategy in the management of AKI.
authors: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Nur
authors: N
authors: Arfian
authors: Noriaki
authors: N
authors: Emoto
authors: Nicolas
authors: N
authors: Vignon-Zellweger
authors: Kazuhiko
authors: K
authors: Nakayama
authors: Keiko
authors: K
authors: Yagi
authors: Ken-ichi
authors: K
authors: Hirata
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics* / Q000473:pathology; D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics*; D000860:Hypoxia / Q000235:genetics; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000096:biosynthesis; D015427:Reperfusion Injury / Q000235:genetics* / Q000473:pathology; D014661:Vasoconstriction / Q000235:genetics
chemical_list: D015820:Cadherins; D019332:Endothelin-1; D017382:Reactive Oxygen Species; D044022:Receptor, Endothelin A; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse