Loss of the alpha-isoform of calcineurin is sufficient to induce nephrotoxicity and altered expression of transforming growth factor-beta

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BACKGROUND. Use of calcineurin inhibitors is frequently limited by fibrosis, closely linked with increased transforming growth factor (TGF)-ß. However, mechanisms of extracellular matrix expansion and TGFß regulation following calcineurin inhibition are unknown. Mice lacking specific calcineurin catalytic subunit isoforms may offer important insight into this pathway. METHODS. We compared mice lacking the α or ß isoform to a model of cyclosporin nephrotoxicity. Histological features common with cyclosporin nephrotoxicity including matrix expansion, arteriole hyalinization, and inflammation were assessed. Next, regulation specifically of fibronectin and TGFß was examined in vivo and in vitro. Finally, the role of TGFß in upregulation of fibronectin with loss of calcineurin activity was examined. RESULTS. Loss of the α isoform results in histologic features and matrix expansion similar to cyclosporin, whereas loss of the ß does not. Fibronectin and TGFß are increased and renal function is impaired in α-null and aged α+/-. In primary α-/- renal fibroblasts, nuclear translocation of the calcineurin substrate NFATc is normal but regulation is lost in ß-null fibroblasts, confirming that the isoforms have distinct functions. Consistent with in vivo findings, α-null cells have increased fibronectin and TGFß. However, neutralizing TGFß antibody did not reduce fibronectin accumulation. CONCLUSIONS. Our data show that calcineurin-α is key to regulation of fibrosis and TGFß and loss of this isoform reproduces features of cyclosporine nephrotoxicity in vivo and in vitro. In addition, we show that upregulation of TGFß and fibronectin likely result from a shared mechanism, but changes in fibronectin expression are independent of TGFß in renal fibroblasts. © 2007 Lippincott Williams & Wilkins, Inc.

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This article was published in Transplantation, Volume 83, Issue 4, Pages 439-447.

The published version is available at http://dx.doi.org/10.1097/01.tp.0000251423.78124.51.

Copyright © 2007 Lippincott.

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