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J. Biol. Chem., Vol. 279, Issue 15, 15561-15570, April 9, 2004

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Involvement of Calcineurin in Transforming Growth Factor--mediated Regulation of Extracellular Matrix Accumulation^*

Jennifer L. Gooch¶, Yves Gorin, Bin-Xian Zhang, and Hanna E. Abboud

From the Department of Medicine, Division of Nephrology, University of Texas Health Science Center, San Antonio, Texas 78284 and the South Texas Veterans Administration, Audie Murphy Memorial Hospital, San Antonio, Texas 78284

Calcineurin is a calcium-dependent, serine/threonine phosphatase that functions as a signaling intermediate. In this study, we investigated the role of calcineurin in transforming growth factor- (TGF-)-mediated cellular effects and examined the signaling pathway involved in activation of calcineurin. Calcineurin is activated by TGF- in a time- and dose-dependent manner. Consistent with increased phosphatase activity, the calcineurin substrate, NFATc1, is dephosphorylated and transported to the nucleus. Inhibition of calcineurin prior to the addition of TGF- revealed that calcineurin is required for TGF--mediated accumulation of extracellular matrix (ECM) proteins but not cell hypertrophy. Conversely, overexpression of constitutively active calcineurin was sufficient to induce ECM protein expression. The mechanism of calcineurin activation by TGF- was found to be induction of a low, sustained increase of intracellular calcium. Chelation of extracellular calcium blocked both TGF--mediated calcium influx and calcineurin activity. Finally, calcium entry was found to be dependent upon generation of reactive oxygen species (ROS) including superoxide anion and hydrogen peroxide. Accordingly, inhibition of ROS generation also blocked TGF--mediated calcineurin phosphatase activity and decreased ECM accumulation. In conclusion, this study describes a new pathway for TGF--mediated regulation of ECM via generation of ROS, calcium influx, and activation of calcineurin.

Received for publication, August 7, 2003 , and in revised form, January 23, 2004.

^* This work was supported by funds from the South Texas Veterans Health Care Administration Research Enhancement Award Program (to J. L. G., Y. G., and H. E. A.), the American Diabetes Association (to J. L. G.), the American Heart Association, National (to Y. G.), the National Institutes of Health (to H. E. A.), and the George O'Brien Kidney Research Center (to J. L. G. and H. E. A.) and by United States Public Health Service Award DK 439888. 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: Renal Division, UTHSCSA, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. E-mail: Gooch{at}uthscsa.edu.

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