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

Kidney Int. 2015 Mar;87(3):535-42. doi: 10.1038/ki.2014.351. Epub 2014 Oct 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects*
  • Adipocytes / metabolism
  • Aged
  • Animals
  • Female
  • Gene Silencing
  • Glucose / metabolism*
  • Humans
  • Hypertension / etiology*
  • Hypertension / metabolism
  • Insulin / pharmacology*
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance / physiology*
  • Kidney Cortex / metabolism
  • Kidney Tubules, Proximal / drug effects*
  • Liver / metabolism
  • Male
  • Metabolic Syndrome / metabolism
  • Middle Aged
  • Phosphatidylinositol 3-Kinase / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred OLETF
  • Rats, Wistar
  • Signal Transduction
  • Sodium-Bicarbonate Symporters / drug effects*
  • Sodium-Bicarbonate Symporters / metabolism
  • Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Irs2 protein, rat
  • RNA, Messenger
  • Sodium-Bicarbonate Symporters
  • Srebf1 protein, rat
  • Sterol Regulatory Element Binding Protein 1
  • Phosphatidylinositol 3-Kinase
  • Glucose