Lisinopril Poster Slides - GTC Diabetes Summit 2015

1. Nephropathy in the ZDSD
rat: Treatment with
Lisinopril
Richard G Peterson, Charles V Jackson and Karen M
Zimmerman.
PreClinOmics, Inc, Indianapolis, IN

2. Abstract:
The purpose of this study was to determine the effectiveness of lisinopril in reducing
albuminuria in ZDSD rats with diabetic nephropathy. The ZDSD rat was developed by
crossing a lean ZDF/Gmi rat with a rat from a sub-colony of CRL:CD(SD) rats. The
obesity is from the CD rat and the pancreatic failure is from the lean ZDF rat. Selective
inbreeding has produced a new obese-diabetic rat model that expresses type II
diabetes in the presence of an intact leptin pathway. Before diabetes develops, the
animals have all of the features of metabolic syndrome including obesity,
hyperlipidemia, hypertension, and insulin resistance, diabetes or pre-diabetes. The
animals become spontaneously diabetic at ~16-30 weeks of age or can be
synchronized to become diabetic with defined diets. In the presence of spontaneous
or diet induced diabetes, they develop progressive albuminuria quickly along with
increases in other urinary markers such as KIM-1, beta-2 microglobulin, Cystatin C,
lipocalin and clusterin. Typical morphological changes of diabetic nephropathy
accompany the marker increases. Lisinopril (ACEi) treatment (30 mg/kg/day) is very
effective in decreasing diabetes-induced albuminuria by about 85% independent of
the duration of diabetes or the initial albumin excretion. Based on these data, the
ZDSD is a very good model of diabetic nephropathy that can be treated with clinically
effective compounds.

3. Methods:
• 18 week-old ZDSD rats were fed a diabetogenic diet (Purina 5SCA) for
2 weeks. Following this induction phase, ZDSD rats were maintained
on regular rodent chow (Purina 5008) for the remainder of study.
• The diabetic ZDSDs were sorted into matched untreated (N=12) and
treated groups (N=13). Treatments were administered by diet
admixture; 5008 or 5008 with Lisinopril, 250 ppm. Based on feed
intake and average body weight, lisinopril was delivered at
approximately 29 mg/kg/day for 4 weeks. Treatment was started 5-13
weeks after ZDSD rats became diabetic
• Blood and urine data were collected before and after 4 weeks of
treatment.
• Glucose, creatinine and BUN were measured in blood; albumin, and
creatinine were measured in urine.
• Responses at four weeks of treatment were compared to vehicle
using Student’s t-tests (p<0.05, *). All data are presented as group
Mean ± SEM.

10. Summary:
1. Lisinopril treatment prevented the progressive rise in
albumin excretion in diabetic ZDSD rats.
2. A worsening of diabetes control and increases in serum
creatinine and BUN were noted during treatment of
diabetic ZDSD rats with Lisinopril. Interestingly, these
effects have also been reported following treatment with
Lisinopril in human patients.
3. The observation that Lisinopril impacts the ZDSD rat with
the same positive (reduced albuminuria) and negative
(increased glucose, creatinine and BUN) effects is a
convincing argument for the translatable characteristics
of the model to the human condition.

11. For more information on models
and contract research services
available at PreClinOmics go to
www.preclinomics.com or
Contact
Richard Peterson
rpeterson@preclinomics.com
Contact
Van Jackson
vjackson@preclinomics.com
317-872-6001