A Novel Type 2 Diabetes Mouse Model of Combined Diabetic Kidney Disease and Atherosclerosis.
A Novel Type 2 Diabetes Mouse Model of Combined Diabetic Kidney Disease and Atherosclerosis.
Am J Pathol. 2017 Nov 15;:
Authors: Bornfeldt KE, Kramer F, Batorsky A, Choi J, Hudkins KL, Tontonoz P, Alpers CE, Kanter JE
Abstract
Diabetic kidney disease and atherosclerotic disease are major causes of morbidity and mortality associated with type 2 diabetes (T2D), and diabetic kidney disease is a major cardiovascular risk factor. The BTBR mouse strain with leptin-deficiency (Lep(ob)) has emerged as one of the best models of human diabetic kidney disease. However, no T2D mouse model of combined diabetic kidney disease and atherosclerosis exists. Our goal was to generate such a model. To this end, the LDL receptor was targeted for degradation via IDOL (inducible degrader of the LDL receptor) overexpression, using a liver-targeted adeno-associated virus (AAV-DJ/8) in BTBR wild-type (WT) and BTBR Lep(ob) (OB) mice. Liver-targeted IDOL-AAV-DJ/8 increased plasma LDL cholesterol, as compared with the control eGFP-AAV-DJ/8. IDOL-induced dyslipidemia caused formation of atherosclerotic lesions of an intermediate stage, which contained both macrophages and smooth muscle cells. BTBR OB mice exhibited diabetic kidney disease. IDOL-induced dyslipidemia worsened albuminuria and glomerular macrophage accumulation, but had no effect on mesangial expansion or podocyte numbers. Thus, by inducing hepatic degradation of the LDL receptor, we generated a T2D m...
Source: The American Journal of Pathology - Category: Pathology Authors: Bornfeldt KE, Kramer F, Batorsky A, Choi J, Hudkins KL, Tontonoz P, Alpers CE, Kanter JE Tags: Am J Pathol Source Type: research
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