Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause.
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(6)C(3)F(1) 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-4alpha1, and matrix metalloproteinase-9 were increased and 3beta-hydroxysteroid dehydrogenase 4 (3beta-HSD4) and transforming growth factor-beta(2) (TGF-beta(2)) were decreased compared with cycling diabetic mice. In peri-OF diabetic mice, mRNA abundance of Egr-1 and 3beta-HSD4 were increased, and TGF-beta(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.
Keck
Maggie
M
Dept. of Physiology, College of Medicine, University of Arizona, Tucson, AZ 85724-5051, USA.
Romero-Aleshire
Melissa J
MJ
Cai
Qi
Q
Hoyer
Patricia B
PB
Brooks
Heddwen L
HL
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D053138:Cyclohexenes / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006728:Hormones / Q000097:blood*; D006801:Humans; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000378:metabolism; D008593:Menopause / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D016649:Primary Ovarian Insufficiency / Q000139:chemically induced / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014753:Vinyl Compounds / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
D001786:Blood Glucose; D053138:Cyclohexenes; D006728:Hormones; D018809:Proliferating Cell Nuclear Antigen; D014753:Vinyl Compounds; C012606:4-vinyl-1-cyclohexene dioxide; D012313:RNA