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Abstract: PO2027

Tacrolimus Induces Ligand-Independent TGF-β Receptor Signaling to Promote Renal Fibrosis

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)


  • Ume, Adaku C., Wright State University Boonshoft School of Medicine, Dayton, Ohio, United States
  • Williams, Clintoria R., Wright State University Boonshoft School of Medicine, Dayton, Ohio, United States

Group or Team Name

  • Kidney Pathophysiology Research Group

Although calcineurin inhibitors (CNIs) such as tacrolimus and cyclosporin have dramatically improved the quality of patient care, long-term therapy causes irreversible damage to the kidneys in the form of renal fibrosis. These morphologic changes ultimately lead to a decline in renal function and can progress to end-stage renal failure. These detrimental outcomes present a critical need to identify the driving mechanisms by which CNIs cause renal damage. It is well established that TGFb is a major contributor to CNI-induced renal fibrosis. However, the underlying mechanisms remain unknown. The objectives of this study are to 1) investigate whether TGFb secretion is required to stimulate TGFb receptor signaling in a model of CNI-induced renal fibrosis and 2) investigate whether calcineurin plays a critical role in regulating TGFb receptor activity.


To examine the role of calcineurin inhibition in altered TGFb receptor signaling, wild type mice were treated with either vehicle (100% ethanol) or 10 mg/kg tacrolimus for 7 days. To confirm in vivo findings, wild-type mouse renal cortical fibroblasts were treated with either vehicle (100% ethanol) or 1nM tacrolimus for 24 hours in the presence and absence of anti-TGFb neutralizing antibodies. TGFb receptor expression and activation, TGFb receptor downstream signaling mediators, profibrotic markers and calcineurin activity were analyzed.


Findings demonstrate that tacrolimus-induced loss of calcineurin activity is accompanied with enhanced TGFb receptor activation and signaling. Notably, increasing concentrations of anti-TGFb neutralizing antibodies failed to abolish aberrant TGFb signaling and increased expression of profibrotic markers.


Together, these results demonstrate that 1) CNIs promote ligand-independent TGFb signaling and 2) calcineurin plays a functional role in regulating TGFb receptor activity.


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