The role of NFkB in calcineurin inhibitor-induced renal fibrosis - Project Abstract/Summary
Calcineurin inhibitors (CNIs) such as CsA and tacrolimus are vital immunosuppressive therapies in the
management of inflammatory conditions such as post-transplantation immunosuppression, lupus nephritis46 and
rare cases of atopic dermatitis47. Although CNIs 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, a concern for both
clinicians and patients. Therefore, the molecular mechanisms by which CNIs induce kidney damage need to be
better understood, and to date, there are no specific therapeutic strategies to mitigate this injury.
There exists therefore, a critical need to explain mechanisms by which CNIs promote renal damage.
Interestingly, loss of CnAα activity in vivo increases markers of renal damage such as TGFβ and
fibronectin3. It is currently unknown which signaling mediators promote the expression of renal damage
markers upon loss of the CnAα isoform. Preliminary data show that exclusive loss of CnAα not only promotes
expression of renal profibrotic markers but also induces NFκB activation. However, the next question,
identifying whether these signaling changes occur via a common pathway, has not yet been answered. This
grant proposal will address this gap in knowledge and test the hypothesis that renal CnAα inhibition
upregulates NFκB signaling, which promotes irreversible renal damage. The expected project outcomes
will characterize CnAα’s role in mediating renal damage through its regulation of NFκB. These findings will
advocate and inspire future development of CnAα-sparing CNIs, ultimately circumventing the nephrotoxicity
noted with long-term CNI use.
To this end, this proposal seeks to I) determine whether NFκB activation promotes renal damage upon
CnAα inhibition and II) determine how renal CnAα inhibition drives NFκB signaling. Successful completion of the
proposed work will identify key mechanisms underlying the nephrotoxic effects of CNIs, thus informing future
development of CnAα-sparing CNIs and/or additional therapies to counter these toxic effects. The long-term goal
will be to mitigate the renal damage and dysfunction noted in patients placed on long-term CNI therapy.
