|M.Sc Student||Abu-Saleh Niroz|
|Subject||Renal Ischemia in an Experimental Diabetic Rat Model: Role|
of Nitric Oxide, Endothelin-1 and
|Department||Department of Medicine||Supervisors||PROF. Zaid A. Abassi|
|PROFESSOR EMERITUS Joseph Winaver|
|Full Thesis text|
Introduction: Ischemic acute renal failure (iARF) in experimental diabetes mellitus (DM) is associated with a rapid deterioration in kidney function, more than in non-diabetic rats. We hypothesize that the impaired renal recovery following ischemia reperfusion in DM is due to dysregulation of the various isoforms of nitric oxide synthase (iNOS and eNOS) combined with enhanced endothelin-1 (ET-1) expression and oxidative stress.
Aims: This study was designed to assess the impact of ischemia on renal function in diabetic compared with non-diabetic; alterations in NOS isoforms in the renal tissue; and involvement of ET-1 and oxidative stress in the pathogenesis of the exaggerated vulnerability of the diabetic kidney to ischemic insult.
Methods: Diabetes mellitus was induced by Streptozotocin. iARF was induced by clamping of left renal artery for 30 min followed by reperfusion in both diabetic and normoglycemic rats. Right intact kidney served as control. 48 hrs following ischemia, clearance protocols were applied to determine renal function: urinary flow (V), sodium excretion (UNaV) and glomerular filtration rate (GFR) in the ischemic and non-ischemic kidneys. Immunoreactivity NOS in the renal tissue were determined 6, 18 and 48 hrs following ischemia and oxidative stress was determined. The contributions of the various NOS isoforms, ET system and oxidative stress to the pathogenesis of the aggravated renal dysfunction were assessed by examining the renal effects of L-NAME, a non selective inhibitor of eNOS, 1400W, an iNOS inhibitor, NPLA, a nNOS inhibitor, ETA antagonist, ETB antagonist, and tempol.
Results: Diabetic rats exhibited increased V reduced UNaV but no change in GFR. iARF in diabetic and nondiabetic rats caused significant reductions in V, UNaV, and GFR. However the deleterious renal effects of iARF were greater in diabetic than non-diabetic rats. eNOS was downregulated in ischemic diabetic kidney more than in injured non-diabetic kidney. In contrast, iNOS significantly increased 6hrs after the ischemic insult in diabetic kidneys, but decreased after 48hrs. Treatment of diabetic rats with L-NAME increased both V and GFR in the ischemic kidney as compared to untreated ischemic diabetic kidney. 1400W slightly improved both V and GFR. ETA antagonist decreased V, and UNaV but increased GFR. In contrast, ETB antagonist and tempol decreased these parameters.
Conclusions: Downregulation of eNOS associated with upregulation of iNOS and excess vasoconstrictive effects of ET-1 by ETA, in combination with elevated oxidative stress, are responsible for the impaired recovery of renal function in the early post-ischemic phase of diabetic rats.