Background: Our earlier human observational studies showed upregulation of de novo lipogenesis (DNL) linked with upregulation of renal acetyl-CoA carboxylase (ACC) encoding genes ACACA and ACACB in progressors of diabetic kidney disease with type 2 diabetes, suggesting that upregulation of renal DNL might be a mechanism of diabetic kidney disease progression in type 2 diabetes. The goal of this project is to generate a transgenic mouse model with conditional knocked out Acaca and Acacb in podocytes and proximal tubular epithelial cells aimed at testing the preservation of renal function and structural histology in the knocked out in vivo model system compared with the wild type diabetic mouse model in future research subject of R01 grant application. Methods: We will utilize a breeding scheme consisting of cross breeding of ACC1/2 flox mice with podocin-Cre and Pepck-Cre mice all on 129SVE background. Outcome: It is expected that by the end of this project we will generate a diabetic mouse model with conditionally knocked out ACC1/2 in podocytes and proximal tubular epithelial cells which then will be ready to test its protective effect against DKD in downstream research.
Emerging evidence suggest that increased synthesis of lipids by kidneys is additional mechanism of progression of kidney disease in diabetes. In this project, we will test, if suppression of acetyl-Co A carboxylase, a key regulatory enzyme responsible for increased fatty acid synthesis preserves kidney function and structure in a diabetic mouse model. We will also test, if a polyunsaturated fatty acid dietary intervention improves the markers of fatty acid synthesis in patients with type 2 diabetes.
