SUN-306 ESTABLISHING EQUIVALENT DIABETES IN MALE AND FEMALE NOS3 DEFICIENT MICE RESULTS IN SIMILAR ONSET OF DIABETIC KIDNEY DISEASE

Abstract

Streptozotocin (STZ)-induced diabetes in male mice lacking endothelial nitric oxide synthase (Nos3-/-) is a widely used model for examining the development of diabetic kidney disease (DKD). Female mice are partially protected from developing STZ-induced diabetes due to their abundance of 17β-estradiol and lack of testosterone, and are not normally used for studies of DKD. In this study, we sought to identify whether male and female Nos3-/- mice with equivalent diabetes develop comparable renal injury, facilitating the potential to use both sexes in studies of DKD. Male and female Nos3-/- mice were made diabetic with 5 or 6 intraperitoneal injections of STZ (55mg/kg/day), respectively. Groups of male and female mice with equivalent diabetes at week 3 after STZ were assessed for diabetic kidney injury (albuminuria, podocyte loss, inflammation, renal function impairment, glomerulosclerosis, tubular injury) at week 8. STZ-treated male and female Nos3-/- mice maintained similar elevated blood glucose levels between weeks 3 and 8 and had equivalent levels of glycated hemoglobin (HbA1c) and hypertension. At week 8, Urine albumin/creatinine levels were increased 8-fold in both diabetic males and females compared to non-diabetic, and were accompanied by a similar (17-20%) loss of podocytes. In diabetic males and females, plasma cystatin-C levels were increased by 33% at week 8, demonstrating similar renal function impairment. Glomerular area of collagen IV immunostaining was also similarly increased by 30% in both genders, signifying equal development of glomerulosclerosis. In addition, kidney mRNA expression of proinflammatory markers (CD68, TNF-α, CCL2), profibrotic markers (TGF-β, Collagen I, Collagen IV, Fibronectin) and KIM-1 were equally elevated in males and females, indicating similar renal inflammation, renal fibrosis and tubular injury. Our study shows that equivalent diabetes induces a similar onset of DKD in male and female Nos3-/- mice, demonstrating it is possible to include males and females together in studies of DKD.