title: Endothelin type A receptor inhibition normalises intrarenal hypoxia in rats used as a model of type 1 diabetes by improving oxygen delivery.
abstract: OBJECTIVE
  Intrarenal tissue hypoxia, secondary to increased oxygen consumption, has been suggested as a unifying mechanism for the development of diabetic nephropathy. Increased endothelin-1 signalling via the endothelin type A receptor (ETA-R) has been shown to contribute to the development of chronic kidney disease, but its role in kidney oxygen homeostasis is presently unknown.
  
  
  METHODS
  The effects of acute ETA-R inhibition (8 nmol/l BQ-123 for 30-40 min directly into the left renal artery) on kidney function and oxygen metabolism were investigated in normoglycaemic control and insulinopenic male Sprague Dawley rats (55 mg/kg streptozotocin intravenously 2 weeks before the main experiment) used as a model of type 1 diabetes.
  
  
  RESULTS
  Local inhibition of ETA-R in the left kidney did not affect BP in either the control or the diabetic rats. As previously reported, diabetic rats displayed increased kidney oxygen consumption resulting in tissue hypoxia in both the kidney cortex and medulla. The inhibition of ETA-Rs restored normal kidney tissue oxygen availability in the diabetic kidney by increasing renal blood flow, but did not affect oxygen consumption. Furthermore, ETA-R inhibition reduced the diabetes-induced glomerular hyperfiltration and increased the urinary sodium excretion. Kidney function in normoglycaemic control rats was largely unaffected by BQ-123 treatment, although it also increased renal blood flow and urinary sodium excretion in these animals.
  
  
  CONCLUSIONS
  Acutely reduced intrarenal ETA-R signalling results in significantly improved oxygen availability in the diabetic kidney secondary to elevated renal perfusion. Thus, the beneficial effects of ETA-R inhibition on kidney function in diabetes may be due to improved intrarenal oxygen homeostasis.
authors.affiliation: Experimental Renal Medicine, Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, 58185, Linköping, Sweden. stephanie.franzen@liu.se.|Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden. stephanie.franzen@liu.se.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Franzén
authors.affiliation: Experimental Renal Medicine, Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, 58185, Linköping, Sweden.|Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden.|Department of Medical Cell Biology, Division of Integrative Physiology, Uppsala University, Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Palm
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects
chemical_list: D065130:Endothelin A Receptor Antagonists; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)
keywords: BQ-123; Diabetic nephropathy; Endothelin type A receptor; Hypoxia; Kidney function; Rats