Serum response factor induces endothelial-mesenchymal transition in glomerular endothelial cells to aggravate proteinuria in diabetic nephropathy.

We investigated the expression and function of serum response factor (SRF) in endothelial-mesenchymal transition (EndMT) in glomerular endothelial cells (GEnCs) of diabetic nephropathy (DN). The expression of SRF, endothelial markers (VE-cadherin, CD31), and mesenchymal markers (α-SMA, FSP-1, fibronectin) was examined in GEnCs following high glucose or in renal cortex tissues of DN rats. SRF was upregulated by SRF plasmids and downregulated by CCG-1423 (a small molecule inhibitor of SRF) to investigate how SRF influenced EndMT in GEnCs of DN. Streptozocin (STZ) was used to generate diabetes mellitus DM in rats. In GEnCs after high glucose treatment and in renal cortex tissues of diabetic rats, SRF, α-SMA, FSP-1, and fibronectin increased, while VE-cadherin and CD31 declined. SRF overexpression in GEnCs induced expression of Snail, an important transcription factor mediating EndMT. Blockade of SRF reduced Snail induction, protected GEnCs from EndMT, and ameliorated proteinuria. Together, increased SRF activity provokes EndMT and barrier dysfunction of GEnCs in DN. Targeting SRF by small molecule inhibitor may be an attractive therapeutic strategy for DN.