The ZDSD rat: a novel model of diabetic nephropathy

Abstract

The ZDSD rat is a new obese-diabetic rat model that expresses type 2 diabetes in the presence of an intact leptin pathway. During a long pre-diabetic state, the animals exhibit most of the features of metabolic syndrome including obesity, hyperlipidemia, hypertension, insulin resistance and decreased glucose disposal. The animals used in these studies were either allowed to become spontaneously diabetic at 16-30 weeks of age, or diabetes was induced with a diabetogenic diet. In the presence of either spontaneous or diet-induced diabetes, they develop progressive albuminuria as well as increases in other urinary markers of impaired renal function (kidney injury molecule-1 (KIM-1), β2-microglobulin, clusterin and cystatin C). Typical morphological changes of nephropathy, such as glomerular capillary basement membrane thickening and podocyte effacement, accompany these marker increases. Lisinopril (ACEi) treatment (30 mg/kg/day via the diet) dramatically reduced diabetes-induced albuminuria by 85%, independent of the duration of diabetes or the initial albumin excretion. These results position the ZDSD rat as a relevant model of diabetic nephropathy that can be treated with clinically effective compounds.

Keywords: Diabetes; kidney; nephropathy; rat; renal.

Figure 1

Weight (A), blood glucose (B) and urinary markers (C-H) of renal injury in ZDSD rats compared to age-matched SD rats. ZDSD rats (■, 10-30 weeks of age) are significantly heavier (A) and have significantly higher blood glucose levels (B) compared to age-matched SD rats (●). Renal injury is evident in ZDSD rats compared to SD rats as evidenced by significantly higher urine volume, albumin excretion and excretion of renal injury biomarkers (C-H) (two-way ANOVA, Sidak’s; *, P<0.05).

Figure 2

Light microscopic pictures of diabetic kidney pathology. The upper panel (A) shows a glomerulus with a nodule in the lower right quadrant of the picture. This glomerulus also demonstrates mesangial expansion (A). The lower panel illustrates sclerosis in two glomeruli and other pathological changes (B).

Figure 3

Electron micrographs of glomerular capillary walls. The picture on the left (A) is from a control kidney while the one on the right (B) is from a ZDSD rat that was diabetic for 12 weeks. The micrographs are aligned with podocytes on the left, and capillary endothelium on the right of the basement membrane. There is a clear thickening of the basement membrane in the diabetic ZDSD when compared to control capillary of age-matched SD rat. (C) represents the quantification of the basement membrane thickness between CD control and ZDSD at 12 weeks and 16.5 weeks of diabetes (155, 158 and 141 measurements, respectively; 6 glomeruli from 2 animals, one-way ANOVA followed by Dunnett’s multiple comparisons test; *P<0.05).

Figure 4

Effect of Lisinopril on urinary albumin excretion in animals with the duration of diabetes. Lisinopril treatment elicited a significant decrease in urinary albumin excretion when compared to vehicle treatment. When stratified according to the duration of diabetes before initiation of treatment, the normalization of albumin excretion by Lisinopril treatment is consistent. All paired groups of animals are significantly different (paired t-test; *P<0.05).