Abstract: TH-PO674

Dyslipidemia Worsens Diabetic Kidney Disease in a Novel Type 2 Diabetes Mouse Model of Combined Kidney Disease and Atherosclerosis – A Possible Role for ApoC-III

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Kanter, Jenny E, University of Washington , Seattle, Washington, United States
  • Kramer, Farah, University of Washington , Seattle, Washington, United States
  • Batorsky, Anna, University of Washington, Seattle, Washington, United States
  • Shao, Baohai, University of Washington, Seattle, Washington, United States
  • Choi, Jinkuk, UCLA, Los Angeles, California, United States
  • Hudkins, Kelly L., University of WA, Seattle, Washington, United States
  • Bornfeldt, Karin, University of Washington , Seattle, Washington, United States
  • Alpers, Charles E., University of Washington Medical Center, Seattle, Washington, United States
Background

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 (Lepob) has emerged as one of the best mouse 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.

Methods

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 wildtype (WT) and BTBR Lepob (OB) mice.

Results

Liver-targeted IDOL-AAV-DJ/8 increased plasma LDL cholesterol, as compared with the control eGFP-AAV-DJ/8 (OB eGFP 194 ± 15 vs OB IDOL 250 ± 10 mg/dl LDL cholesterol). 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 albumin/creatinine ratio (885 ± 96 μg/mg in OB eGFP vs 1681 ± 391μg/mg in OB IDOL) and glomerular macrophage accumulation (1.9 ± 0.4 Mac-2 positive cells/glomerulus in OB eGFP vs 3.5 ± 0.7 in OB IDOL) and cortex inflammation (increased expression of Ccl2, Il1b and Vcam1 comparing OB IDOL to OB eGFP), but had no effect on mesangial expansion or podocyte numbers. Furthermore, HDL-associated apolipoprotein C-III (apoC-III) was elevated in OB mice compared with WT mice and this was further increased by IDOL-induced dyslipidemia. ApoC-III in turn correlated positively with both atherosclerosis and albuminuria.

Conclusion

Thus, by inducing hepatic degradation of the LDL receptor, we generated a T2D model of combined kidney disease and atherosclerosis in which dyslipidemia may worsen the kidney disease, potentially through elevated apoC-III. This model provides a new tool to study mechanisms, interactions, and treatment strategies of diabetic kidney disease and atherosclerosis.

Funding

  • NIDDK Support