title: Involvement of the endothelin and nitric oxide systems in the pathogenesis of renal ischemic damage in an experimental diabetic model.
abstract: OBJECTIVE
  Ischemic acute kidney injury (iAKI) in experimental diabetes mellitus (DM) is associated with a rapid kidney dysfunction more than in non-diabetic rats. We hypothesize that this vulnerability is due to excessive endothelin-1 (ET-1) expression along with dysregulation of nitric oxide synthase (NOS) isoforms. The aim of the present study was to assess the impact of ischemia on renal function in diabetic rats as compared with non-diabetic rats, and to investigate the involvement of ET-1 and NO systems in the susceptibility of diabetic kidney to ischemic damage.
  
  
  METHODS
  DM was induced by Streptozotocin. iAKI was induced by clamping of left renal artery for 30 min. Right intact kidney served as control. 48 h following ischemia, clearance protocols were applied to assess glomerular filtration rate (GFR), urinary flow (V) and sodium excretion (U(Na)V) in both kidneys. The renal effects of ABT-627, ET(A) antagonist; A192621.1, ET(B) antagonist; L-NAME, NOS non-selective inhibitor; 1400 W, inducible NOS (iNOS) inhibitor; and NPLA, neuronal NOS (nNOS) inhibitor, were assessed following ischemic renal injury in diabetic rats.
  
  
  RESULTS
  Induction of iAKI in diabetic and non-diabetic rats caused significant reductions in GFR, V, and U(Na)V, which were greater in diabetic than non-diabetic rats. While, treatment with ABT-627 decreased V and U(Na)V, and increased GFR, A192621.1 decreased all these parameters. L-NAME, 1400 W, and NPLA improved GFR in the ischemic diabetic kidney.
  
  
  CONCLUSIONS
  Excessive vasoconstrictive effects of ET-1 via ET(A) and upregulation of iNOS, are partly responsible for the impaired recovery of renal function following ischemia in diabetic rats.
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine, Technion, IIT, Haifa, Israel.
authors.forename: Niroz
authors.initials: N
authors.lastname: Abu-Saleh
authors.forename: Elena
authors.initials: E
authors.lastname: Ovcharenko
authors.forename: Hoda
authors.initials: H
authors.lastname: Awad
authors.forename: Ilia
authors.initials: I
authors.lastname: Goltsman
authors.forename: Mogher
authors.initials: M
authors.lastname: Khamaisi
authors.forename: Aaron
authors.initials: A
authors.lastname: Hoffman
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Heyman
authors.forename: Joseph
authors.initials: J
authors.lastname: Winaver
authors.forename: Zaid
authors.initials: Z
authors.lastname: Abassi
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000503:physiopathology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D019332:Endothelin-1 / Q000378:metabolism*; D005919:Glomerular Filtration Rate; D008297:Male; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism*; D015427:Reperfusion Injury / Q000503:physiopathology; D013311:Streptozocin; D015854:Up-Regulation; D014661:Vasoconstriction
chemical_list: D019332:Endothelin-1; D044022:Receptor, Endothelin A; D009569:Nitric Oxide; D013311:Streptozocin; D052247:Nitric Oxide Synthase Type II