Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome

Motonobu Nakamura, Osamu Yamazaki, Ayumi Shirai, Shoko Horita, Nobuhiko Satoh, Masashi Suzuki, Yoshifumi Hamasaki, Eisei Noiri, Haruki Kume, Yutaka Enomoto, Yukio Homma, George Seki

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Hyperinsulinemia can contribute to hypertension through effects on sodium transport. To test whether the stimulatory effect of insulin on renal proximal tubule sodium transport is preserved in insulin resistance, we compared the effects of insulin on abdominal adipocytes and proximal tubules in rats and humans. Insulin markedly stimulated the sodium-bicarbonate cotransporter (NBCe1) activity in isolated proximal tubules through the phosphoinositide 3-kinase (PI3-K) pathway. Gene silencing in rats showed that while insulin receptor substrate (IRS)1 mediates the insulin effect on glucose uptake into adipocytes, IRS2 mediates the insulin effect on proximal tubule transport. The stimulatory effect of insulin on glucose uptake into adipocytes was severely reduced, but its stimulatory effect on NBCe1 activity was completely preserved in insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats and patients with insulin resistance. Despite widespread reduction of IRS1 and IRS2 expression in insulin-sensitive tissues, IRS2 expression in the kidney cortex was exceptionally preserved in both OLETF rats and patients with insulin resistance. Unlike liver, acute insulin injection failed to change the expression levels of IRS2 and sterol regulatory element-binding protein 1 in rat kidney cortex, indicating that regulatory mechanisms of IRS2 expression are distinct in liver and kidney. Thus, preserved stimulation of proximal tubule transport through the insulin/IRS2/PI3-K pathway may play an important role in the pathogenesis of hypertension associated with metabolic syndrome.

Original languageEnglish
Pages (from-to)535-542
Number of pages8
JournalKidney international
Volume87
Issue number3
DOIs
Publication statusPublished - 2015 Mar 1

Keywords

  • IRS1
  • IRS2
  • NBCe1
  • insulin resistance
  • proximal tubule
  • siRNA

ASJC Scopus subject areas

  • Nephrology

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    Nakamura, M., Yamazaki, O., Shirai, A., Horita, S., Satoh, N., Suzuki, M., Hamasaki, Y., Noiri, E., Kume, H., Enomoto, Y., Homma, Y., & Seki, G. (2015). Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome. Kidney international, 87(3), 535-542. https://doi.org/10.1038/ki.2014.351