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PMID: 18495798 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Protein kinase B/Akt activity is involved in renal TGF-beta1-driven epithelial-mesenchymal transition in vitro and in vivo.

American journal of physiology. Renal physiology ·Vol. 295 ·No. 1 ·2008-07-00 ·Pages F215-25

Kattla JJ, Carew RM, Heljic M, Godson C, Brazil DP

Abstract

The molecular pathogenesis of diabetic nephropathy (DN), the leading cause of end-stage renal disease worldwide, is complex and not fully understood. Transforming growth factor-beta (TGF-beta1) plays a critical role in many fibrotic disorders, including DN. In this study, we report protein kinase B (PKB/Akt) activation as a downstream event contributing to the pathophysiology of DN. We investigated the potential of PKB/Akt to mediate the profibrotic bioactions of TGF-beta1 in kidney. Treatment of normal rat kidney epithelial cells (NRK52E) with TGF-beta1 resulted in activation of phosphatidylinositol 3-kinase (PI3K) and PKB/Akt as evidenced by increased Ser473 phosphorylation and GSK-3beta phosphorylation. TGF-beta1 also stimulated increased Smad3 phosphorylation in these cells, a response that was insensitive to inhibition of PI3K or PKB/Akt. NRK52E cells displayed a loss of zona occludins 1 and E-cadherin and a gain in vimentin and alpha-smooth muscle actin expression, consistent with the fibrotic actions of TGF-beta1. These effects were blocked with inhibitors of PI3K and PKB/Akt. Furthermore, overexpression of PTEN, the lipid phosphatase regulator of PKB/Akt activation, inhibited TGF-beta1-induced PKB/Akt activation. Interestingly, in the Goto-Kakizaki rat model of type 2 diabetes, we also detected increased phosphorylation of PKB/Akt and its downstream target, GSK-3beta, in the tubules, relative to that in control Wistar rats. Elevated Smad3 phosphorylation was also detected in kidney extracts from Goto-Kakizaki rats with chronic diabetes. Together, these data suggest that TGF-beta1-mediated PKB/Akt activation may be important in renal fibrosis during diabetic nephropathy.

MeSH Terms
Animals Cell Transdifferentiation/physiology Chromones/pharmacology Diabetes Mellitus, Experimental/physiopathology Diabetes Mellitus, Type 2/physiopathology Diabetic Nephropathies/pathology,physiopathology Dimethyl Sulfoxide/pharmacology Epithelial Cells/drug effects,physiology Kidney/cytology,drug effects Mesenchymal Stem Cells/drug effects,physiology Morpholines/pharmacology Proto-Oncogene Proteins c-akt/physiology Rats Transforming Growth Factor beta1/physiology
Chemicals
Chromones Morpholines Transforming Growth Factor beta1 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one Proto-Oncogene Proteins c-akt Dimethyl Sulfoxide
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Kattla Jayesh J
UCD Diabetic Research Centre, School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland.
Carew Rosemarie M
Heljic Mediha
Godson Catherine
Brazil Derek P
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Article Info
Journal
American journal of physiology. Renal physiology
Abbr.
Am J Physiol Renal Physiol
ISSN
1931-857X
DOI
10.1152/ajprenal.00548.2007
Published
2008-07-00
Epub
2008-00-21
Pages
F215-25
Language
English
Region
United States
NLM ID
100901990
PMCID
PMC2494512
Subset
IM
Grants
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 10.1152/ajprenal.00548.2007 PMC Full Text View journal details
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