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

21 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
Externally publishedYes

Fingerprint

Insulin Resistance
Insulin
Hypertension
Inbred OLETF Rats
Adipocytes
Kidney Cortex
1-Phosphatidylinositol 4-Kinase
Sodium-Bicarbonate Symporters
Sodium
Sterol Regulatory Element Binding Protein 1
Insulin Receptor Substrate Proteins
Glucose
Proximal Kidney Tubule
Liver
Hyperinsulinism
Gene Silencing
Kidney
Injections

Keywords

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

ASJC Scopus subject areas

  • Nephrology

Cite this

Nakamura, M., Yamazaki, O., Shirai, A., Horita, S., Satoh, N., Suzuki, M., ... 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

Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome. / Nakamura, Motonobu; Yamazaki, Osamu; Shirai, Ayumi; Horita, Shoko; Satoh, Nobuhiko; Suzuki, Masashi; Hamasaki, Yoshifumi; Noiri, Eisei; Kume, Haruki; Enomoto, Yutaka; Homma, Yukio; Seki, George.

In: Kidney International, Vol. 87, No. 3, 01.03.2015, p. 535-542.

Research output: Contribution to journalArticle

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, vol. 87, no. 3, pp. 535-542. https://doi.org/10.1038/ki.2014.351
Nakamura, Motonobu ; Yamazaki, Osamu ; Shirai, Ayumi ; Horita, Shoko ; Satoh, Nobuhiko ; Suzuki, Masashi ; Hamasaki, Yoshifumi ; Noiri, Eisei ; Kume, Haruki ; Enomoto, Yutaka ; Homma, Yukio ; Seki, George. / Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome. In: Kidney International. 2015 ; Vol. 87, No. 3. pp. 535-542.
@article{8be6df1c20444cbaa69351fe49565923,
title = "Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome",
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.",
keywords = "insulin resistance, IRS1, IRS2, NBCe1, proximal tubule, siRNA",
author = "Motonobu Nakamura and Osamu Yamazaki and Ayumi Shirai and Shoko Horita and Nobuhiko Satoh and Masashi Suzuki and Yoshifumi Hamasaki and Eisei Noiri and Haruki Kume and Yutaka Enomoto and Yukio Homma and George Seki",
year = "2015",
month = "3",
day = "1",
doi = "10.1038/ki.2014.351",
language = "English",
volume = "87",
pages = "535--542",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome

AU - Nakamura, Motonobu

AU - Yamazaki, Osamu

AU - Shirai, Ayumi

AU - Horita, Shoko

AU - Satoh, Nobuhiko

AU - Suzuki, Masashi

AU - Hamasaki, Yoshifumi

AU - Noiri, Eisei

AU - Kume, Haruki

AU - Enomoto, Yutaka

AU - Homma, Yukio

AU - Seki, George

PY - 2015/3/1

Y1 - 2015/3/1

N2 - 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.

AB - 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.

KW - insulin resistance

KW - IRS1

KW - IRS2

KW - NBCe1

KW - proximal tubule

KW - siRNA

UR - http://www.scopus.com/inward/record.url?scp=84928006369&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84928006369&partnerID=8YFLogxK

U2 - 10.1038/ki.2014.351

DO - 10.1038/ki.2014.351

M3 - Article

C2 - 25354240

AN - SCOPUS:84928006369

VL - 87

SP - 535

EP - 542

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 3

ER -