title: ROCK1 Induces Endothelial-to-Mesenchymal Transition in Glomeruli to Aggravate Albuminuria in Diabetic Nephropathy.
abstract: 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 α-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 α-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.
authors: Department of Internal Medicine, Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
authors: Hui
authors: H
authors: Peng
authors: Department of Internal Medicine, Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
authors: Yuanqing
authors: Y
authors: Li
authors: Department of Internal Medicine, Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
authors: Cheng
authors: C
authors: Wang
authors: Department of Internal Medicine, Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
authors: Jun
authors: J
authors: Zhang
authors: Department of Internal Medicine, Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
authors: Yanru
authors: Y
authors: Chen
authors: Department of Pathology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
authors: Wenfang
authors: W
authors: Chen
authors: Department of Medicine, Nephrology Division, Baylor College of Medicine, Houston, Texas, 77030-3411, U.S.
authors: Jin
authors: J
authors: Cao
authors: Department of Medicine, Nephrology Division, Baylor College of Medicine, Houston, Texas, 77030-3411, U.S.
authors: Yanlin
authors: Y
authors: Wang
authors: Department of Medicine, Nephrology Division, Baylor College of Medicine, Houston, Texas, 77030-3411, U.S.
authors: Zhaoyong
authors: Z
authors: Hu
authors: Department of Internal Medicine, Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
authors: Tanqi
authors: T
authors: Lou
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000199:Actins / Q000378:metabolism; D000419:Albuminuria / Q000188:drug therapy / Q000209:etiology*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000150:complications / Q000473:pathology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010539:Permeability / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012171:Retinal Vessels / Q000166:cytology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D005947:Glucose; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D054460:rho-Associated Kinases; D000099152:Cadherin 5; C544013:alpha-smooth muscle actin, mouse; C515851:ROCK1 protein, human; C049347:fasudil