Insulin increases the activity of mesangial BK channels through MAPK signaling

Ruth M. Foutz, P. Richard Grimm, Steven C. Sansom

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Abstract

Glomerular hyperfiltration and mesangial expansion have been described in mouse models of a hyperinsulinemic early stage of type 2 diabetes mellitus (DM). Large-conductance Ca2+-activated K+ channels (BK) have been linked to relaxation of human mesangial cells (MC) and may contribute to MC expansion and hyperfiltration. We hypothesized that high insulin levels increase BK activity in MC by increasing the number and/or open probability (Po) of BK in the plasma membrane. With the use of the patch-clamp technique, BK activity was analyzed in cultured MC exposed to normal insulin (1 nM) and high insulin (100 nM) for a 48-h period. The mean Po and the percentage of patches (cell attached) with detected BK increased by 100% in the insulin-treated cells. Real-time PCR revealed that insulin increased mRNA of BK-α. Western blot revealed an insulin-stimulated increase in BK-α from both total cellular and plasma membrane protein fractions. The mitogen-activated protein kinase (MAPK) inhibitors PD-098059 and U-0126 attenuated the insulin-induced increase in BK-α expression. PD-098059 inhibited insulin-stimulated phosphorylation of extracellular signal-regulated kinase 1/2 in MC. An insulin-stimulated increase also was found for total cellular BK-β1, the accessory subunit of BK in MC. A similar increase in BK-α mRNA and protein was evoked by an insulin-like growth factor I analog. Glomeruli, isolated from hyperinsulinemic early stage type 2 DM mice, exhibited increased BK-α mRNA by real-time PCR and protein by immunohistochemical staining and Western blot. These results indicate that insulin activates BK in the plasma membrane of MC and stimulates, via MAPK, an increase in cellular and plasma membrane BK-α.

Original languageEnglish (US)
Pages (from-to)F1465-F1472
JournalAmerican Journal of Physiology - Renal Physiology
Volume294
Issue number6
DOIs
Publication statusPublished - Jun 1 2008

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Keywords

  • High-fat diet
  • Insulin-like growth factor I
  • Insulin-like growth factor I receptor
  • Maxi k
  • Mouse
  • Potassium channel
  • β-subunit

ASJC Scopus subject areas

  • Physiology
  • Urology

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