Mouse Model for Study of Diabetic Nephropathy and Role of Soluble Epoxide Hydrolase

Diabetic nephropathy (DN) is the leading cause of renal failure and is characterized by proteinuria that progresses to renal inflammation and decline in the glornerular filtration barrier (GFB). Podocytes are specialized epithelia cells in the glomerular capsule that have a role in filtration of blood and maintaining the integrity of the GFB; dysfunction of these cells plays a significant role in the pathogenesis of DN. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition has beneficial effects in inflammatory diseases.

In the present invention, mice with a podocyte-specific deletion of sEH (pod-sEHKO) were generated to determine the effects of podocyte sEH on renal function. These mice showed moderate improvement in kidney function and systemic glucose homeostasis in normoglycemia and a significant improvement in hyperglycemia. Histology of the kidneys of these animals and in vitro assays with mouse podocytes treated with an sEH inhibitor, confirmed that sEH in podocytes is a key contributor to kidney function and systemic glucose homeostasis. These findings demonstrate that pharmacological and gene-based sEH inhibitors can be used to improve kidney function and blood pressure and protect podocytes from hyperglycemia-induced injury, thus inhibiting or preventing DN.

This invention was co-developed with the University of California at Davis.