Abstract 13443: Pre-Emptive Hemin Therapy Improves Glucose Metabolism and Suppress Diabetic Nephropathy in the First Generation Offspring of Diabetic Rats by Modulating Histone Residues
Epigenetic modifications of genes can induce novel and beneficial changes that are transcended across different generations. We investigated whether pre-emptive upregulation of heme-oxygenase (HO-1) would reverse the detrimental fetal-programming in F1-generation born from diabetic mothers, and if the epigenetic modifications of histone are involved. HO was induced with hemin or blocked with stannous-mesoporphyrin (SnMP) in pregnant Goto-Kakizaki rats, a model of type-2 diabetes characterized by elevated endothelin-1 (ET-1)/oxidative stress, impaired insulin-signaling/glucose metabolism and diabetic nephropathy. In adult F1-generation born from hemin-treated mothers, fasting/postprandial hyperglygemia, gastrocnemius/plasma (endothelin) ET-1, 8-isoproatane, pro-inflammatory/oxidative mediators including TNF-α, IL-6, IL-1β, NF-κB, cJNK, proteinuria, albuminuria and albuminuria-to-creatinine index were reduced while adiponectin and creatinine clearance increased, suggesting improved renal function. These were accompanied by increased AMPK, GLUT4, aldolase-B with reduced glucose/insulin tolerance and insulin resistance (HOMA-IR). Correspondingly, enhanced HO-1, HO-activity, cGMP, cAMP, bilirubin, ferritin, SOD and the total-antioxidant capacity were observed, whereas in F1-generation born from mothers co-treated with hemin and the HO-blocker, SnMP these effects were abolished. Furthermore, we detected several changes in histone expression including H4K9-acetyl, H3K9-acetyl, H3K9-phosphate, H3K9-dimethyl and H2BK9-acetyl, suggesting a role of acetylated, phosphorylated and methylated histones in the hemin-induced changes. These results suggest that pre-emptive upregulation of the HO system in pregnant GK rats with hemin positively impact the health-status of offspring. The hemin-mediated remediation of impaired glucose metabolism and renal deficiency, and the subsequent transcendence from parents to offspring may be due to epigenetic changes as alterations of histone, a protein central to chromatin modification were observed.
- © 2011 by American Heart Association, Inc.