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, Koichi Hayashi, H. Itoh

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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.

元の言語English
ページ(範囲)1062-1071
ページ数10
ジャーナルInternational Journal of Obesity
36
発行部数8
DOI
出版物ステータスPublished - 2012 8

ASJC Scopus subject areas

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

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    Tokuyama, H., Wakino, S., Hara, Y., Washida, N., Fujimura, K., Hosoya, K., Yoshioka, K., Hasegawa, K., Minakuchi, H., Homma, K., Hayashi, K., & Itoh, H. (2012). Role of mineralocorticoid receptor/Rho/Rho-kinase pathway in obesity-related renal injury. International Journal of Obesity, 36(8), 1062-1071. https://doi.org/10.1038/ijo.2011.232