Is the Zucker Diabetic Fat Rat an Appropriate Model of Diabetic Kidney Disease: A Discussion on Hydronephrosis
Authors: McDermott Amy , Panduro Nathalie , Taghavi Iman , Kjer Hans Martin , Søgaard Stinne Byrholdt , Jensen Jørgen Arendt , Sørensen Charlotte Mehlin 
Published: May 2024

Introduction: Kidney disease is a significant concern for global healthcare, particularly in individuals with diabetes. Experimental research into the pathology of diabetes is dependent on the utilisation of appropriate animal models. The Zucker Diabetic Fat (ZDF) rat has a Leptin receptor deficiency and is a commonly used model of type 2 diabetes. Here, we examine the relevance of this model for the investigation of diabetic kidney disease, with a particular focus on vascular imaging. The Zucker Lean (ZL) rat is a non-diabetic strain of the same rat lineage and will be used as a control. Method: This dataset used the ZDF rat (n=13) and the Zucker Lean (ZL) rat (n=16). Individuals were scanned at ages of 12 weeks (ZDF n=4, ZL n=4), 22 weeks (ZDF n=4, ZL n=5), and 40 weeks (ZDF n=5, ZL n=7). During open laparotomy, rats were maintained on a respirator under general anaesthesia via isoflurane and blood pressure was monitored via a central catheter. During surgery, a blood glucose measurement was taken from the tail vein and samples of arterial blood and urine were collected. The contrast medium Microfil (MV122, Flow Tech Inc., Carver, MA) was injected post-mortem via the renal artery and excised kidneys were scanned for 11 hours in a ZEISS XRadia 410 Versa μCT scanner (Carl Zeiss Microscopy GmbH, Jena, Germany). Results: As expected, the ZDF rats developed significant hyperglycaemia from 12 weeks, significant increases in albumin creatinine ratio (ACR) from 22 weeks, and a significant decrease in glomerular filtration rate (GFR) from 40 weeks. Concurrent hydronephrosis affecting more than 10% of total kidney volume was detected in 51% of all rats (group prevalence rates were ZDF=69% and ZL=38%). The percent of the kidney mass affected by hydronephrosis was significantly higher in ZDF than ZL (ANOVA row factor p=0,029*). Age had no significant impact on the size of the hydronephrotic cavity. There was a significant correlation between the degree of hyperglycaemia and the size of the hydronephrotic cavity (mm) (r=0.57, p=0,0014**). ACR, GFR and urine excretion rate were unaffected by hydronephrosis. Hydronephrosis did not have a significant impact on vascular density in the remaining kidney tissue (p=0.53). Conclusion: The high prevalence of hydronephrosis development in the ZDF rat questions its appropriateness to model human diabetic kidney disease, as hydronephrosis is not commonly seen in diabetic patients. While vascular density was preserved in the remaining kidney tissue, the huge loss of vascular tissue caused by hydronephrotic erosion means this model is limited for all renal imaging applications. Both ZDF and ZL rats develop hydronephrosis suggesting this may be a genetic condition of their common lineage. However, the conditions' increased severity in the ZDF rat indicates that the deficit in the leptin receptor contributes to disease pathology. The significant relationship between hyperglycaemia and hydronephrosis size suggests the two conditions are interacting, raising questions about whether the underlying molecular mechanisms of this model of diabetic kidney disease have any relevance for translational research. Funded by European Research Council Synergy grant SURE, project no. 854796. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.