Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans

Kozi Hosoya, Hitoshi Minakuchi, Shu Wakino, Keiko Fujimura, Kazuhiro Hasegawa, Motoaki Komatsu, Ayumi Yoshifuji, Koji Futatsugi, Keisuke Shinozuka, Naoki Washida, Takeshi Kanda, Hirobumi Tokuyama, Koichi Hayashi, Hiroshi Itoh

研究成果: Article査読

23 被引用数 (Scopus)

抄録

In this study, we examined the association between chronic kidney disease (CKD) and insulin resistance. In a patient cohort with nondiabetic stages 2-5 CKD, estimated glomerular filtration rate (eGFR) was negatively correlated and the plasma aldosterone concentration was independently associated with the homeostasis model assessment of insulin resistance. Treatment with the mineralocorticoid receptor blocker spironolactone ameliorated insulin resistance in patients, and impaired glucose tolerance was partially reversed in fifth/sixth nephrectomized rats. In these rats, insulin-induced signal transduction was attenuated, especially in the adipose tissue. In the adipose tissue of nephrectomized rats, nuclear mineralocorticoid receptor expression, expression of the mineralocorticoid receptor target molecule SGK-1, tissue aldosterone content, and expression of the aldosterone-producing enzyme CYP11B2 increased. Mineralocorticoid receptor activation in the adipose tissue was reversed by spironolactone. In the adipose tissue of nephrectomized rats, asymmetric dimethylarginine (ADMA; an uremic substance linking uremia and insulin resistance) increased, the expression of the ADMA-degrading enzymes DDAH1 and DDAH2 decreased, and the oxidative stress increased. All of these changes were reversed by spironolactone. In mature adipocytes, aldosterone downregulated both DDAH1 and DDAH2 expression, and ADMA inhibited the insulin-induced cellular signaling. Thus, activation of mineralocorticoid receptor and resultant ADMA accumulation in adipose tissue has, in part, a relevant role in the development of insulin resistance in CKD.

本文言語English
ページ(範囲)749-760
ページ数12
ジャーナルKidney international
87
4
DOI
出版ステータスPublished - 2015 4 8

ASJC Scopus subject areas

  • Nephrology

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