title: Esculetin induced changes in Mmp13 and Bmp6 gene expression and histone H3 modifications attenuate development of glomerulosclerosis in diabetic rats.
abstract: Esculetin, an antioxidant, has been used in the treatment of a variety of diseases. This study aimed to investigate the protective effect of esculetin in attenuating streptozotocin (STZ)-induced type I diabetic nephropathy and to understand the molecular mechanism involved in it. Sprague-Dawley rats were rendered diabetic using a single dose of STZ (55 mg/kg, i.p.). Protein expression of PPARγ and transforming growth factor-β1 (TGF-β1) was detected by immunoblotting and immunohistochemistry respectively. RNA expression levels of Mmp13 and Bmp6 were detected by RT-PCR analysis. In diabetic rats, esculetin treatment resulted in a significant decrease in blood glucose, blood urea nitrogen, and plasma creatinine and increase in plasma albumin levels. Esculetin treatment attenuates the downregulation of PPARγ in diabetic kidney, which in turn blocks the TGF-β1-mediated fibronectin expression. In addition, it attenuates the decrease in mono-methylation (K4) and acetylation of histone H3 in diabetic kidney. RT-PCR analysis revealed that esculetin treatment provides protection by decreasing antifibrotic Bmp6 and increasing fibrogenic Mmp13 mRNA expression in diabetic kidney. This is the first report to show that protection observed by esculetin treatment involves alteration in mRNA expression of Mmp13 and Bmp6 genes either directly via altered histone H3 modifications or indirectly by inhibiting the PPARγ/TGF-β1 pathway.
authors: Laboratory of Chromatin Biology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, SAS Nagar, Mohali, Punjab 160 062, India.
authors: Vivek Madhukar
authors: VM
authors: Surse
authors: Jeena
authors: J
authors: Gupta
authors: Kulbhushan
authors: K
authors: Tikoo
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000123:Acetyltransferases / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D055418:Bone Morphogenetic Protein 6 / Q000187:drug effects / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications; D003928:Diabetic Nephropathies / Q000503:physiopathology / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D006657:Histones / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000187:drug effects / Q000235:genetics*; D008745:Methylation / Q000187:drug effects; D008780:Methyltransferases / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014468:Umbelliferones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; C525818:Bmp6 protein, rat; D055418:Bone Morphogenetic Protein 6; D006657:Histones; D047495:PPAR gamma; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014468:Umbelliferones; D013311:Streptozocin; D008780:Methyltransferases; D000123:Acetyltransferases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; C007628:esculetin