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Abstract: FR-OR16

Set7 Lysine Methyltransferase Influences Endothelial to Mesenchymal Transition in Experimental Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • El-Osta, Assam, Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia

Group or Team Name

  • Human Epigenetics

Diabetic nephropathy (DN) is the number one cause of renal failure with therapeutic options to prevent its progression limited. In response to hyperglycaemia, the lysine methyltransferase Set7 is known to regulate inflammation and fibrosis, however, its role in DN remains poorly understood. This study defines unique endothelial to mesenchymal transition in experimental diabetic nephropathy.


Set7-/- constitutive knockout mice were back crossed with ApoE-/- to accelerate DN. Streptozotocin (STZ) administration was used to induce diabetes with subsequent renal injury in Set7-/-ApoE-/- mice over five consecutive days (referred now as diabetic Set7KO). Single cell RNA-seq (scRNA-seq) was used to identify the major renal cell types modified by hyperglycaemia. The selective inhibitor of the Set7 methyltransferase, PFI-2, was used to determine the generalizability in human proximal tubule cells (PTC), glomerular endothelial (GEN) and podocyte (PDC) cells.


Diabetic Set7KO mice had improved urinary albumin excretion and glomerular pathology. Assessments of the transcriptome revealed endothelial-to-mesenchymal transition was predictive of diabetic injury using scRNA-seq. Gene expression changes dependent on Set7 regulation were identified in PTC, GEN, PDC and mesenchymal (MSC) cells. Network analyses of diabetic renal injury identified pathways dependent on Set7 involve respiratory electron transport (RET), rRNA processing, extracellular matrix organisation (EMO) and peroxisome proliferator activated receptor alpha (PPARa). Because scRNA-seq identified GEN, PDC and PTC populations as major cell types regulated by Set7 involved in diabetic injury, we extended studies to hyperglycaemic human renal cells using PFI-2, a pharmacological Set7 inhibitor. Pathways associated with diabetic injury in mice which are improved by genetic Set7 deletion closely correspond with Set7 inhibition using PFI-2 in human PTC, GEN and podocyte cells.


These findings support the rationale of targeting Set7 activity as a strategy for developing reno-protective therapies in diabetes. Our studies also show the MSC gene markers upregulated by diabetes in mice were attenuated in human GEN cells by PFI-2 and implicate Set7 in endothelial to mesenchymal transition.


  • Government Support – Non-U.S.