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Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Joan C. Krepinsky^*, Yanxia Li^*, Yanfei Chang^*, Lieqi Liu^*, Fangfang Peng^*, Dongcheng Wu^*, Damu Tang^*, James Scholey and Alistair J. Ingram^*

^* Department of Medicine, Division of Nephrology, McMaster University, Hamilton, Canada; and Department of Medicine, University of Toronto, Canada

Address correspondence to: Dr. Joan C. Krepinsky, Saint Joseph’s Hospital, 50 Charlton Avenue E., Room F544A, Hamilton, ON, L8N 4A6, Canada. Phone: 905-522-1155 ext. 4991; Fax: 905-521-6068; E-mail: krepinj{at}mcmaster.ca

Received for publication October 31, 2004. Accepted for publication February 23, 2005.

Increased glomerular hydrostatic pressure is an important determinant of glomerulosclerosis and can be modeled by in vitro exposure of mesangial cells to cyclic mechanical strain. Stretched mesangial cells increase extracellular matrix protein production, the hallmark of glomerulosclerosis. Recent data indicate that the serine/threonine kinase Akt may be involved in matrix modulation. Thus, Akt activation and matrix synthesis in stretched mesangial cells were studied. Exposure of mesangial cells to 1 Hz cyclic strain led to prompt Akt activation, which was biphasic to 24 h. Activation was dependent on signaling through phosphatidylinositol-3-kinase and required EGF receptor transactivation. Inhibition of signaling through the PDGF receptor, Src kinase, or cytoskeletal disruption failed to prevent strain-induced Akt activation. Collagen type 1A1 transcript expression, promoter activation, and protein secretion were increased by stretch at 24 h and were dependent on phosphatidylinositol-3 kinase. Overexpression of dominant-negative Akt inhibited strain-induced collagen 1A1 production. Conversely, overexpression of constitutively active Akt led to increased collagen 1A1 upregulation and secretion. Finally, Akt activation was observed in the glomeruli of remnant rat kidneys, a model marked by increased intraglomerular pressure. The authors conclude that mechanical strain induces Akt activation in mesangial cells through a mechanism requiring phosphatidylinositol-3-kinase and EGF receptor transactivation. Type 1 collagen production is dependent on Akt and can be induced by Akt overexpression. Akt activation is observed in remnant kidneys in vivo. Thus, the role of Akt in progression of chronic hemodynamic glomerular disease is worthy of further exploration.

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