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Updated: Aug 30, 2026
Modeling and Evaluation of Murine Diabetic Cardiomyopathy Model
Published on: November 29, 2024
Nephropathy in a hypercholesterolemic mouse model with streptozotocin-induced diabetes
Samar M Hammad1, Debra J Hazen-Martin, Mimi Sohn
1Division of Endocrinology, Diabetes, and Medical Genetics, Medical University of South Carolina, Charleston 29425, USA. hammadsm@musc.edu
Background/Aims:
The contribution of preexisting hypercholesterolemia to diabetic nephropathy remains unclear. We assessed the impact of hypercholesterolemia on diabetic nephropathy using a double knockout (DKO) mouse, null for the low-density lipoprotein receptor (LDLRNDASH;/NDASH;) and the apoB mRNA editing catalytic polypeptide 1 (APOBEC1NDASH;/NDASH;).
Methods:
Wild-type (WT) and DKO mice received sham or streptozotocin injections at age 7 weeks, yielding control (WT-C, DKO-C) and diabetic (WT-D, DKO-D) groups. At sacrifice (age 40 weeks), albuminuria was determined by ELISA, and kidney sections were examined by light and electron microscopy.
Results:
Albuminuria increased in diabetic mice (WT-D: 82.4 +/- 37.2 microg/18 h; DKO-D: 58.0 +/- 45.7 microg/18 h) versusnondiabetic controls (WT-C: 10.2 +/- 7.2 microg/18 h; DKO-C: 8.6 +/- 5.3 microg/18 h) (p LT; 0.0001), but was unaffected by hypercholesterolemia. Light microscopy of kidney sections demonstrated increased collagen levels in glomeruli in WT-D mice, but not in DKO-D mice or either control group. Electron microscopy showed a thickened glomerular basement membrane in WT-D mice only. The proximal tubular basement membrane thickness was increased in both diabetic groups versusnondiabetic controls (p LT; 0.01); in WT-D mice this was attributable to collagen accumulation, but in DKO-D mice it was mainly caused by lipid vacuoles.
Conclusions:
In this animal model, preexisting hypercholesterolemia did not exacerbate either glomerular lesions of diabetes (collagen accumulation, basement membrane thickening) or albuminuria, but appeared to mitigate these effects. Furthermore, the combination of hypercholesterolemia and diabetes resulted in a significant lipid accumulation in the tubular basement membrane.
Insights
Preexisting hypercholesterolemia did not worsen diabetic kidney disease in mice. Instead, it appeared to mitigate glomerular damage and albuminuria, but increased lipid accumulation in the tubular basement membrane.
Area of Science:
- Nephrology
- Metabolic Disorders
- Animal Models
Background:
- Diabetic nephropathy is a major complication of diabetes, and the role of hypercholesterolemia is not fully understood.
- This study investigates the impact of hypercholesterolemia on diabetic kidney disease using a unique mouse model.
Purpose of the Study:
- To determine if preexisting hypercholesterolemia exacerbates diabetic nephropathy.
- To analyze the effects of hypercholesterolemia on glomerular and tubular changes in diabetic kidneys.
Main Methods:
- A double knockout (DKO) mouse model lacking the low-density lipoprotein receptor and apoB mRNA editing enzyme was used.
- Mice were made diabetic using streptozotocin, and kidney tissues were analyzed for albuminuria, collagen deposition, basement membrane thickness, and lipid accumulation.
Main Results:
- Diabetes increased albuminuria in both wild-type and DKO mice, with no significant effect of hypercholesterolemia.
- Diabetic wild-type mice showed increased glomerular collagen and thickened glomerular basement membranes, which were not observed in DKO diabetic mice.
- Both diabetic groups exhibited thickened proximal tubular basement membranes, attributed to collagen in wild-type and lipid vacuoles in DKO mice.
Conclusions:
- Preexisting hypercholesterolemia did not worsen diabetic kidney disease markers like albuminuria or glomerular lesions in this model.
- Hypercholesterolemia appeared to have a mitigating effect on glomerular damage in diabetic mice.
- The combination of hypercholesterolemia and diabetes led to significant lipid accumulation in the tubular basement membrane.
