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

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)749-760
Number of pages12
JournalKidney international
Volume87
Issue number4
DOIs
Publication statusPublished - 2015 Apr 8

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Keywords

  • ADMA
  • Aldosterone
  • CKD
  • Insulin resistance
  • Mineralocorticoid receptor

ASJC Scopus subject areas

  • Nephrology

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