A Novel Type 2 Diabetes Mouse Model of Combined Diabetic Kidney Disease and
Authors Bornfeldt KE, Kramer F, Batorsky A, Choi J, Hudkins KL, Tontonoz P, Alpers CE,
Kanter JE
Submitted By Charles Alpers on 2/19/2018
Status Published
Journal The American journal of pathology
Year 2018
Date Published 2/1/2018
Volume : Pages 188 : 343 - 352
PubMed Reference 29154962
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 black and tan,
brachyury (BTBR) mouse strain with leptin deficiency (Lepob) 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 low-density lipoprotein (LDL) receptor
was targeted for degradation via inducible degrader of the LDL receptor (IDOL)
overexpression, using liver-targeted adenoassociated virus serotype DJ/8
(AAV-DJ/8) in BTBR wild-type and BTBR Lepobmice. Liver-targeted IDOL-AAV-DJ/8
increased plasma LDL cholesterol compared with the control enhanced green
fluorescent protein AAV-DJ/8. IDOL-induced dyslipidemia caused formation of
atherosclerotic lesions of an intermediate stage, which contained both
macrophages and smooth muscle cells. BTBR Lepobmice 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 model of combined kidney disease and atherosclerosis. This model provides
a new tool to study mechanisms, interactions, and treatment strategies of kidney
disease and atherosclerosis in T2D.