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J. Biol. Chem., Vol. 279, Issue 4, 2632-2639, January 23, 2004

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The Phosphatidylinositol 3-Kinase/Akt Pathway Enhances Smad3-stimulated Mesangial Cell Collagen I Expression in Response to Transforming Growth Factor-1^*

Constance E. Runyan, H. William Schnaper, and Anne-Christine Poncelet

From the Department of Pediatrics, Northwestern University, Chicago, Illinois 60611

Transforming growth factor (TGF)- has been associated with renal glomerular matrix accumulation. We previously showed that Smad3 promotes COL1A2 gene activation by TGF-1 in human glomerular mesangial cells. Here, we report that the PI3K/Akt pathway also plays a role in TGF-1-increased collagen I expression. TGF-1 stimulates the activity of phosphoinositide-dependent kinase (PDK)-1, a downstream target of PI3K, starting at 1 min. Akt, a kinase downstream of PDK-1, is phosphorylated and concentrates in the membrane fraction within 5 min of TGF-1 treatment. The PI3K inhibitor LY294002 decreases TGF-1-stimulated 1(I) and 2(I) collagen mRNA expression. Similarly, LY294002 or an Akt dominant negative construct blocks TGF-1 induction of COL1A2 promoter activity. However, PI3K stimulation alone is not sufficient to increase collagen I expression, since neither a constitutively active p110 PI3K construct nor PDGF, which induces Akt phosphorylation, is able to stimulate COL1A2 promoter activity or mRNA expression, respectively. LY294002 inhibits stimulation of COL1A2 promoter activity by Smad3. In a Gal4-LUC assay system, blockade of the PI3K pathway significantly decreases TGF-1-induced transcriptional activity of Gal4-Smad3. Activity of SBE-LUC, a Smad3/4-responsive construct, is stimulated by over-expression of Smad3 or Smad3D, in which the three C-terminal serine phospho-acceptor residues are mutated. This induction is blocked by LY294002, suggesting that inhibition of the PI3K pathway decreases Smad3 transcriptional activity independently of C-terminal serine phosphorylation. However, TGF-1-induced total serine phosphorylation of Smad3 is decreased by LY294002, suggesting that Smad3 is phosphorylated by the PI3K pathway at serine residues other than the direct TGF- receptor I target site. Thus, although the PI3K-PDK1-Akt pathway alone is insufficient to stimulate COL1A2 gene transcription, its activation by TGF-1 enhances Smad3 transcriptional activity leading to increased collagen I expression in human mesangial cells. This cross-talk between the Smad and PI3K pathways likely contributes to TGF-1 induction of glomerular scarring.

Received for publication, September 22, 2003 , and in revised form, November 6, 2003.

^* This work was supported by a Young Investigator Research Grant from the National Kidney Foundation of Illinois (to A.-C. P.), Grant DK49362 from the National Institute of Diabetes, Digestive and Kidney Disease (to H. W. S.); and the Children's Memorial Institute for Education and Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Northwestern University, Dept. of Pediatrics, W-140, Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611-3008. Tel.: 312-503-0089; Fax: 312-503-1181; E-mail: anne-c{at}northwestern.edu.

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