Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2016

Genetic deletion of the Set7 lysine methyltransferase attenuates renal damage in a mouse model of diabetic nephropathy (#128)

Hanah Rodriguez 1 2 , Bryna Chow 3 , Mark Ziemann 1 , Karin Jandeleit-Dahm 3 , Mark Cooper 3 , Mrinal Bhave 2 , Assam El-Osta 1
  1. Epigenetics in Human Health and Disease, Baker IDI, Melbourne, VIC
  2. Faculty of Science, Engineering and Technology, Swinburne University of Technology, Melbourne, VIC
  3. Diabetic Complications Laboratory, Department of Diabetes, Monash University, Melbourne, VIC

Chronic hyperglycaemia promotes the production of pro-inflammatory and pro-fibrotic mediators that lead to the development of chronic kidney disease. Increasing evidence implicates epigenetic modifications, particularly histone methylation, in this process. Set7, a lysine methyltransferase that mono-methylates histone (Lys4 on histone H3) and non-histone proteins, has been associated with increased expression of pro-fibrotic genes in various models of kidney disease. This project aims to further define the role of Set7 in the development of diabetic nephropathy and evaluate it as a target for developing reno-protective therapies in diabetes. For this purpose, diabetes-induced structural and functional kidney damage was studied in ApoE-/- and Set7-/-/ApoE-/- male mice compared to non-diabetic controls. ApoE-/- mice were used as they develop a more severe disease phenotype under diabetic conditions. Mice were euthanised after 10 weeks of streptozotocin-induced diabetes and kidneys were harvested for molecular and histological analyses. 24-hour urine samples were also collected from all mice before euthanasia. Set7 deletion conferred renal protection as evidenced by attenuated albuminuria, mesangial expansion scores and glomerular deposition of collagen I and IV in diabetic Set7-/-/ApoE-/- when compared to diabetic ApoE-/- mice. Moreover, the expression of pro-fibrotic and pro-inflammatory genes such as Fn1 and Icam1 was also attenuated in the kidneys of diabetic Set7-/-/ApoE-/- mice and this was associated with reduced H3K4me1 levels at their promoters. Global renal cortical gene expression by RNA-seq followed by pathway analysis revealed that Set7 is associated with pathways related to mitochondrial function in diabetic mice. Furthermore, analysis of the H3K4me1 profile shows a global reduction in the levels of this histone mark near gene transcriptional start sites and enhancers in diabetic Set7-/-/ApoE-/- compared to diabetic ApoE-/- mice. Collectively, our results suggest that targeting Set7 may represent a strategy for developing therapies aimed at reducing the burden of diabetic nephropathy.