title: Amelioration of albuminuria in ROCK1 knockout mice with streptozotocin-induced diabetic kidney disease.
abstract: BACKGROUND
  Although blockade of Rho kinase with pharmacologic inhibitors ameliorates renal fibrosis and diabetic kidney disease (DKD), the underlined mechanisms remain largely unclear. The present study tested the hypothesis that ROCK1 may regulate the early development of albuminuria via the megalin/cubilin-dependent mechanism.
  
  
  METHODS
  A DKD model was induced in ROCK1 knockout and wild-type mice by streptozotocin (STZ). The effect of deleted ROCK1 on urinary albumin excretion and the expression of megalin/cubilin were examined. In addition, the effect of blocking ROCK activities with an inhibitor (Y-27632) on tubular albumin reabsorption was tested in a normal rat tubular epithelial cell line (NRK52E) under high-glucose conditions. Expression of transforming growth factor (TGF)-β1, interleukin-1β and collagen-1 was also been examined.
  
  
  RESULTS
  Urinary albumin excretion was significantly increased in ROCK1 WT mice at 8 weeks after STZ injection. In contrast, mice lacking ROCK1 gene were protected against the development of albuminuria. This was associated with the protection against the loss of megalin/cubilin and an increase in TGF-β(1), IL-1β, and fibrosis in the kidney. In vitro, we also found that blockade of Rho kinase with inhibitor Y-27632 prevented high-glucose-induced loss of megalin expression and an increase of TGF-β(1), thereby increasing the absorption rate of FITC-labeled albumin by tubular epithelial cells.
  
  
  CONCLUSIONS
  ROCK1 may play a role in the development of albuminuria in DKD by downregulating the endocytosis receptors complex - megalin/cubilin.
authors: Department of Medicine-Nephrology, West China Hospital of Sichuan University, Chengdu, China.
authors: Li
authors: L
authors: Zhou
authors: Fei
authors: F
authors: Liu
authors: Xiao R
authors: XR
authors: Huang
authors: Fang
authors: F
authors: Liu
authors: Haiyong
authors: H
authors: Chen
authors: Arther C K
authors: AC
authors: Chung
authors: Jianjian
authors: J
authors: Shi
authors: Lei
authors: L
authors: Wei
authors: Hui Y
authors: HY
authors: Lan
authors: Ping
authors: P
authors: Fu
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control; D000577:Amides / Q000494:pharmacology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D000577:Amides; D011725:Pyridines; C108830:Y 27632; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases