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AMP‐activated Protein Kinase (AMPK) regulates TGF‐β1 Induced Fibronectin Expression in Renal Tubular Epithelial Cells
Author(s) -
Thakur Sachin,
Viswanadhapalli Suryavathi,
Gorin Yves,
Abboud Hanna E
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.601.10
Subject(s) - ampk , fibronectin , amp activated protein kinase , protein kinase a , microbiology and biotechnology , phosphorylation , gene knockdown , chemistry , medicine , cancer research , extracellular matrix , endocrinology , biology , apoptosis , biochemistry
Tubulointerstitial fibrosis is a main pathological feature of progressive renal disease. Transforming growth factor beta (TGF‐β) induces mesencymal cell characteristics in tubular epithelial cells including increased expression of fibronectin and α‐smooth muscle actin (α‐SMA). We report that in cultured murine and primary human proximal tubular epithelial cells (PTECs), TGF‐β results in a decrease in AMPK phosphorylation on active site (Thr 172 ) associated with increased fibronectin and α‐SMA. Activation of AMPK with AICAR or metformin or overexpression of constitutively active AMPK markedly reduced TGF‐β‐induced fibronectin and α‐SMA. Conversely, inhibition of AMPK with ARA or AMPK knockdown by siRNA enhanced basal as well as TGF‐β‐induced fibronectin and α‐SMA. The decrease in AMPK phosphorylation with TGF‐β was accompanied by a decrease in tuberin phosphorylation on Ser 1387 , the AMPK phosphorylated site that keeps tuberin active. Moreover, tuberin knockdown by siRNA in PTECs enhanced basal as well TGF‐β‐induced fibronectin and α‐SMACollectively, the data indicate that TGF‐β exerts its profibrotic actions via inactivation of AMPK and tuberin, and that AMPK activation attenuates PTECs injury. Our results suggest that AMPK activation represents a potential therapeutic target to prevent mesenchymal cell transition including extracellular matrix accumulation in progressive renal disease. This work was supported by NIH‐NIDDK grant RO1 DK078971 to HEA.