ROCK1 Induces Endothelial-to-Mesenchymal Transition in Glomeruli to Aggravate Albuminuria in Diabetic Nephropathy

Endothelial-to-mesenchymal transition (EndMT) can cause loss of tight junctions, which in glomeruli are associated with albuminuria. Here we evaluated the role of EndMT in the development of albuminuria in diabetic nephropathy (DN). We demonstrated that EndMT occurs in the glomerular endothelium of patients with DN, showing by a decrease in CD31 but an increase in alpha-SMA expression. In glomeruli of db/ db mice, there was an increased ROCK1 expression in the endothelium plus a decreased CD31-positive cells. Cultured glomerular endothelial cells (GEnCs) underwent EndMT when stimulated by 30 mM glucose, and exhibited increased permeability. Meanwhile, they showed a higher ROCK1 expression and activation. Notably, inhibition of ROCK1 largely blocked EndMT and the increase in endothelial permeability under this high-glucose condition. In contrast, overexpression of ROCK1 induced these changes. Consistent alterations were observed in vivo that treating db/db mice with the ROCK1 inhibitor, fasudil, substantially suppressed the expression of a-SMA in the glomerular endothelium, and reduced albuminuria. Thus we conclude that ROCK1 is induced by high glucose and it stimulates EndMT, resulting in increased endothelial permeability. Inhibition of ROCK1 could be a therapeutic strategy for preventing glomerular endothelial dysfunction and albuminuria in developing DN.