ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

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)

Authors

  • 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
Background

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.

Methods

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.

Results

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.

Conclusion

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

Funding

  • NIDDK Support