Journal
TRANSPLANTATION
Volume 83, Issue 4, Pages 439-447Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.tp.0000251423.78124.51
Keywords
cyclosporin; fibrosis; TGF beta
Categories
Funding
- NIDDK NIH HHS [R01 DK066422-02] Funding Source: Medline
Ask authors/readers for more resources
Background. Use of calcineurin inhibitors is frequently limited by fibrosis, closely linked with increased transforming growth factor (TGF)-beta. However, mechanisms of extracellular matrix expansion and TGF beta 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 alpha or beta 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 TGF beta was examined in vivo and in vitro. Finally, the role of TGF beta in upregulation of fibronectin with loss of calcineurin activity was examined. Results. Loss of the a isoform results in histologic features and matrix expansion similar to cyclosporin, whereas loss of the beta does not. Fibronectin and TGF beta are increased and renal function is impaired in alpha-null and aged alpha+/-. In primary alpha-/- renal fibroblasts, nuclear translocation of the calcineurin substrate NFATc is normal but regulation is lost in beta-null fibroblasts, confirming that the isoforms have distinct functions. Consistent with in vivo findings, alpha-null cells have increased fibronectin and TGF beta. However, neutralizing TGF beta antibody did not reduce fibronectin accumulation. Conclusions. Our data show that calcineurin-a is key to regulation of fibrosis and TGF beta and loss of this isoform reproduces features of cyclosporine nephrotoxicity in vivo and in vitro. In addition, we show that upregulation of TGF beta and fibronectin likely result from a shared mechanism, but changes in fibronectin expression are independent of TGF beta in renal fibroblasts.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available