Role of mineralocorticoid receptor/Rho/Rho-kinase pathway in obesity-related renal injury

H. Tokuyama, S. Wakino, Y. Hara, N. Washida, K. Fujimura, K. Hosoya, K. Yoshioka, K. Hasegawa, H. Minakuchi, K. Homma, K. Hayashi, H. Itoh

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Abstract

OBJECTIVE: We examined whether aldosterone/Rho/Rho-kinase pathway contributed to obesity-associated nephropathy.SUBJECTS: 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.CONCLUSION: 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.

Original languageEnglish
Pages (from-to)1062-1071
Number of pages10
JournalInternational Journal of Obesity
Volume36
Issue number8
DOIs
Publication statusPublished - 2012 Aug 1

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Keywords

  • MCP1
  • SGK1
  • adipose tissue
  • aldosterone
  • metabolic syndrome

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics

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