title: Role of mineralocorticoid receptor/Rho/Rho-kinase pathway in obesity-related renal injury.
abstract: OBJECTIVE
  We examined whether aldosterone/Rho/Rho-kinase pathway contributed to obesity-associated nephropathy.
  
  
  METHODS
  C57BL/6J mice were fed a high fat or low fat diet, and mice on a high fat diet were treated with a mineralocorticoid receptor antagonist, eplerenone.
  
  
  RESULTS
  The mice on a high fat diet not only developed obesity, but also manifested renal histological changes, including glomerular hypercellularity and increased mesangial matrix, which paralleled the increase in albuminuria. Furthermore, enhanced Rho-kinase activity was noted in kidneys from high fat diet-fed mice, as well as increased expressions of inflammatory chemokines. All of these changes were attenuated by eplerenone. In high fat diet-fed mice, mineralocorticoid receptor protein levels in the nuclear fraction and SGK1, an effector of aldosterone, were upregulated in kidneys, although serum aldosterone levels were unaltered. Furthermore, aldosterone and 3β-hydroxysteroid dehydrogenase in renal tissues were upregulated in high fat diet-fed mice. Finally, in cultured mesangial cells, stimulation with aldosterone enhanced Rho-kinase activity, and pre-incubation with eplerenone prevented the aldosterone-induced activation of Rho kinase.
  
  
  CONCLUSIONS
  Excess fat intake causes obesity and renal injury in C57BL/6J mice, and these changes are mediated by an enhanced mineralocorticoid receptor/Rho/Rho-kinase pathway and inflammatory process. Mineralocorticoid receptor activation in the kidney tissue and the subsequent Rho-kinase stimulation are likely to participate in the development of obesity-associated nephropathy without elevation in serum aldosterone levels.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tokuyama
authors.forename: S
authors.initials: S
authors.lastname: Wakino
authors.forename: Y
authors.initials: Y
authors.lastname: Hara
authors.forename: N
authors.initials: N
authors.lastname: Washida
authors.forename: K
authors.initials: K
authors.lastname: Fujimura
authors.forename: K
authors.initials: K
authors.lastname: Hosoya
authors.forename: K
authors.initials: K
authors.lastname: Yoshioka
authors.forename: K
authors.initials: K
authors.lastname: Hasegawa
authors.forename: H
authors.initials: H
authors.lastname: Minakuchi
authors.forename: K
authors.initials: K
authors.lastname: Homma
authors.forename: K
authors.initials: K
authors.lastname: Hayashi
authors.forename: H
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D000077545:Eplerenone; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D007668:Kidney / Q000293:injuries / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009765:Obesity / Q000473:pathology*; D018384:Oxidative Stress; D015398:Signal Transduction; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054460:rho-Associated Kinases / Q000187:drug effects* / Q000235:genetics
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D000451:Mineralocorticoid Receptor Antagonists; D014409:Tumor Necrosis Factor-alpha; D013148:Spironolactone; D000077545:Eplerenone; D054460:rho-Associated Kinases