A NOVEL HYPOPERFUSION-INDUCED ACUTE KIDNEY INJURY MODEL IN DIABETIC RATS.
David Nikolic-paterson1 1Monash Health, Clayton, VIC, Australia
Abstract
Aim: To develop a model of reduced mean arterial pressure (MAP) in diabetic rats.
Background: Acute kidney injury (AKI) often occurs in high-risk patients (e.g. diabetic) following hypoperfusion during cardiopulmonary bypass (CPB) surgery. However, little is known of hypoperfusion-induced pathologic changes and how diabetes makes the kidney vulnerable to this insult. By contrast, standard ischaemia/reperfusion (I/R) models of AKI use renal artery clamping in healthy animals.
Methods: 6 weeks after establishment of STZ-induced diabetes in outbred Sprague Dawley rats, renal hypoperfusion was induced by lowering MAP to 55.4±2.5 mmHg for 60 min (mimicking hypoperfusion occurring during CPB surgery) via an adjustable aortic occluder in diabetic or control non-diabetic rats. Animals were killed 1, 7, or 28 days after surgery (n=3-6/group).
Results: Hypoperfusion induced mild tubular dilation, a slight increase in Kim1 expression, but no change in plasma creatinine on day 1 in control rats, with full structural repair seen on day 7. By contrast, day 1 diabetic/hypoperfusion rats showed increased plasma creatinine (86.3±12.8 vs 38.0±4.2umol/L in control hypoperfusion; P<0.001) on day 1, with widespread tubular dilatation (cortex and medulla) with epithelial cell flattening but little necrosis, increased Kim1 expression, and reduced Pgc1a indicating mitochondrial dysfunction (all P<0.01 vs control hypoperfusion). Gene expression of markers of tubular damage (Kim1), inflammation (Ccl2, Cd68) and fibrosis (Col1a1, Tgfb1, Fn1) peaked on day 7 in diabetes/hypoperfusion, with increased interstitial deposition of collagen I evident on day 28. These findings contrast with the primary lesion of tubular necrosis in standard I/R models.
Conclusions: The combination of diabetes and hypoperfusion can induce AKI, consistent with clinical observations in CPB surgery, and shows a very different pathology to the standard I/R model.
Biography
Dr Nikolic-Paterson investigates potential therapies to target cell death, inflammation and fibrosis in acute and chronic kidney disease. This includes developing new animal models to examine the impact of comorbidities on susceptibility to acute kidney injury and the transition to chronic kidney disease.
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