Diabetic Kidney Disease in the VCD Model of Menopause

Abstract

Kidney disease is a major complication of diabetes and accounts for one-third of all diabetes-related deaths. Estrogen is considered protective against cardiovascular and non-diabetic renal disease, however it is unclear if this protection extends to diabetes and diabetic kidney disease.To address these questions, we have used a new model of menopause in which repeated daily injections of 4-vinylcyclohexene (VCD) induces gradual ovarian failure in mice. Unlike with ovariectomy, the VCD model preserves the gradual transition into ovarian failure (OF) (modeling perimenopause). Also, following OF, the residual ovarian tissue is retained and secretes androgens, similar to the androgen production by postmenopausal human ovaries.The VCD model of menopause was combined with the streptozotocin (STZ) model of type 1 diabetes, and the development of diabetes and diabetic kidney damage were studied over the subsequent 6 weeks. We observed that blood glucose levels are higher in post-OF diabetic mice compared to cycling diabetic and peri-OF diabetic mice. Renal cell proliferation, an early marker of kidney damage, is increased in post-OF diabetic mice compared to cycling diabetic mice, as measured by expression of proliferating cell nuclear antigen. We also demonstrate that expression of α-smooth muscle actin is increased in post-OF diabetic mice compared to cycling diabetic mice. Five weeks after STZ injection, post-OF diabetic mice had higher rates of urine albumin excretion than cycling diabetic mice.Using real-time PCR, we identified changes in expression between post-OF diabetic and cycling diabetic mice of genes which have previously been associated with diabetic kidney damage. We also show that some of these changes occur in peri-OF diabetic mice as well. Using microarray, we identified 119 new genes which are regulated by the combination of ovarian failure and diabetes in the mouse kidney.These data support our hypothesis that the changes in hormones which occur during the transition into ovarian failure exacerbate the development and progression of diabetic kidney damage in mice. These data also highlight the utility and importance of the VCD model of menopause in the study of diabetic kidney damage.