Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause

Abstract

Changes in the estrogen/testosterone balance at menopause may negatively influence the development of diabetic kidney disease. Furthermore, recent studies suggest that changes in hormone levels during perimenopause may influence disease development. Injection of 4-vinylcyclohexene diepoxide (VCD) in B 6C3F1 mice induces gradual ovarian failure, preserving both the perimenopausal (peri-ovarian failure) and menopausal (post-ovarian failure) periods. To address the impact of the transition into menopause on the development of diabetes and diabetic kidney damage, we used streptozotocin (STZ)-induced diabetes in the VCD model of menopause. After 6 wk of STZ-induced diabetes, blood glucose was significantly increased in post-ovarian failure (post-OF) diabetic mice compared with cycling diabetic mice. In peri-ovarian failure (peri-OF) diabetic mice, blood glucose levels trended higher but were not significantly different from cycling diabetic mice, suggesting a continuum of worsening blood glucose across the menopausal transition. Cell proliferation, an early marker of damage in the kidney, was increased in post-OF diabetic mice compared with cycling diabetic mice, as measured by PCNA immunohistochemistry. In post-OF diabetic mice, mRNA abundance of early growth response-1 (Egr-1), collagen-4␣1, and matrix metalloproteinase-9 were increased and 3␤-hydroxysteroid dehydrogenase 4 (3␤-HSD4) and transforming growth factor-␤2 (TGF-␤2) were decreased compared with cycling diabetic mice. In peri-OF diabetic mice, mRNA abundance of Egr-1 and 3␤-HSD4 were increased, and TGF-␤2 was decreased compared with cycling diabetic mice. This study highlights the importance and utility of the VCD model of menopause, as it provides a physiologically relevant system for determining the impact of the menopausal transition on diabetes and diabetic kidney damage. diabetes; 3␤-HSD4; perimenopause; real-time PCR; estrogen DIABETES IS ONE OF THE MOST prevalent and costly diseases afflicting developed countries, with estimates placing the current global cost of diabetes at $150 billion a year (1). Approximately one-third of all diabetics die of end-stage renal disease (33) due to progressive renal damage and hypertension.17␤-Estradiol is considered protective against the development and progression of many diseases, including cardiovascular (9) and renal disease (34). Premenopausal women have slower rates of progression of nondiabetic renal disease than age-matched men (23), a difference that seems to disappear after menopause (3). The impact of estrogen on diabetic renal disease is less clear, however. Several studies demonstrate a decreased incidence of diabetic renal disease in women, but others have found no difference between men and women (34).The 5-10 years preceding menopause is termed perimenopause, and during this time estrogen levels fluctuate, with periods of low estrogen interspersed with periods of very high estrogen (31). The periods of low estrogen become more frequent as a woman approaches menopause until circulating levels of 17␤...

ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause

“…We demonstrated that VCD-treated mice given a high-fat diet gained significantly more weight and had impaired glucose tolerance compared with cycling female mice on a high-fat diet. Diabetic kidney damage also accelerates more rapidly in female mice when diabetes is induced during menopause compared with perimenopause (15). Together our data suggest that inclusion of the perimenopause period for mechanistic evaluations will likely be a useful tool to investigate the subsequent susceptibility to disease onset and progression.…”

Age at menarche and the risk of diabetic microvascular complications in patients with type 1 diabetes

“…Further evidence for a link between hormonal status and risk of microvascular complications associated with type 1 diabetes was provided by a study showing that women with diabetic retinopathy and nephropathy undergo menopause at an earlier age [37]. Several experimental studies have demonstrated a renoprotective role for exogenous oestrogens in models of type 1 diabetic retinopathy and nephropathy [38][39][40]. It is possible that early onset of diabetes impairs the ovarian production of oestrogen, thus becoming permissive for the development of organ complications later in life.…”

Predictors of diabetic nephropathy

“…Experiments done in mice were successful in identifying estrogens as an important factor retarding the progression of kidney disease [12,13], in contrast to testosterone that aggravates it [14]. Intrigued with such findings, a recent study by Möllsten et al investigated the elements of gender and age as risk factors of CKD progression in patients with type 1 diabetes [15].…”