AMP-activated protein kinase (AMPK) activation inhibits nuclear translocation of Smad4 in mesangial cells and diabetic kidneys

Jinghong Zhao, Satoshi Miyamoto, Young Hyun You, Kumar Sharma

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Diabetic nephropathy is characterized by diffuse mesangial matrix expansion and is largely dependent on the TGF-b/Smad signaling pathway. Smad4 is required for TGF-b signaling; however, its regulation has not been well characterized in diabetic kidney disease. Here, we report that high glucose is sufficient to stimulate nuclear translocation of Smad4 in mesangial cells and that stimulation of the major energy sensor AMP-activated protein kinase (AMPK) has a potent effect to block Smad4 nuclear translocation. Activation of AMPK by 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside (AICAR) inhibited high glucose-induced and TGF-b stimulation of nuclear Smad4. To identify which of the catalytic α-subunits may be involved, small interfering (si) RNA-based inhibition of AMPK α1- or α2-subunit was employed. Inhibition of either subunit reduced overall AMPK activity and contributed to Smad4 nuclear accumulation. In an animal model of early diabetic kidney disease, induction of diabetes was found to markedly stimulate Smad4 protein levels and enhance nuclear accumulation. AMPK activation with AICAR completely prevented the upregulation of Smad4 and reduced mesangial matrix accumulation. We conclude that stimulation of Smad4 in cell culture and in in vivo models of early diabetic kidney disease is dependent on AMPK.

Original languageEnglish
Pages (from-to)F1167-F1177
JournalAmerican Journal of Physiology - Renal Physiology
Volume308
Issue number10
DOIs
Publication statusPublished - May 15 2015
Externally publishedYes

Fingerprint

AMP-Activated Protein Kinases
Mesangial Cells
Diabetic Nephropathies
Aminoimidazole Carboxamide
Smad4 Protein
Glucose
Small Interfering RNA
Catalytic Domain
Up-Regulation
Animal Models
Cell Culture Techniques

Keywords

  • AICAR
  • AMP-activated protein kinase
  • Diabetic nephropathy
  • High glucose
  • Smad4

ASJC Scopus subject areas

  • Physiology
  • Urology
  • Medicine(all)

Cite this

AMP-activated protein kinase (AMPK) activation inhibits nuclear translocation of Smad4 in mesangial cells and diabetic kidneys. / Zhao, Jinghong; Miyamoto, Satoshi; You, Young Hyun; Sharma, Kumar.

In: American Journal of Physiology - Renal Physiology, Vol. 308, No. 10, 15.05.2015, p. F1167-F1177.

Research output: Contribution to journalArticle

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