The TWEAK/Fn14 pathway is required for calcineurin inhibitor toxicity of the kidneys

Abstract

Calcineurin inhibitor toxicity (CNT) is a frequent occurrence in transplanted renal grafts and autochthone kidneys from patients undergoing long-term treatment with calcineurin inhibitors, notably cyclosporin A (CsA) and tacrolimus. Here, we show an indispensable role of the tumor necrosis factor superfamily (TNFS) molecule TNF-related weak inducer of apoptosis (TWEAK) (TNFSF12) in the pathogenesis of acute CNT lesions in mice. A deficiency in TWEAK resulted in limited tubulotoxicity after CsA exposure, which correlated with diminished expression of inflammatory cytokines and reduced intraparenchymal infiltration with immune cells. We further identified tubular epithelial cells of the kidney as major targets of CsA activity and found that Fn14 (tumor necrosis factor receptor superfamily 12A), the receptor for TWEAK, is a highly CsA-inducible gene in these cells. Correlating with this, CsA pretreatment sensitized tubular epithelial cells specifically to the pro-inflammatory activities of recombinant TWEAK in vitro. Moreover, injection of rTWEAK alone into mice induced moderate disease similar to CsA, and rTWEAK combined with CsA resulted in synergistic nephrotoxicity. These findings support the importance of tubular epithelial cells as cellular targets of CsA toxicity and introduce TWEAK as a critical contributor to CNT pathogenesis.

A Low Tacrolimus Concentration/Dose Ratio Increases the Risk for the Development of Acute Calcineurin Inhibitor-Induced Nephrotoxicity

“…In our cell culture model, the viability of NRK tubular epithelial cells significantly decreased when cells were incubated with Tac according to the PK profiles of fast metabolizers (Figure 6). These most affected cells notably expressed the highest amount of Fn14, a receptor protein known to be involved in the pathogenesis of CNIT [3]. It has to be considered that due to the robustness of NRK cells we applied Tac concentrations that are supra-therapeutic compared to Tac blood concentrations that are observed in patients and a direct translation into clinical practice and exact modelling of patients’ Tac exposure, which is much more complex and influenced by many factors in vivo, is limited.…”

“…As fibroblast growth factor-inducible 14 (Fn14) is involved in the pathogenesis of CNIT we analyzed its expression in Tac-treated NRK cells using primary antibodies against α-actinin 4 and Fn14, respectively [3].…”

“…While acute CNIT comprises isometric tubular vacuolization, acute arteriolopathy, and thrombotic microangiopathy, the features of chronic CNIT include interstitial fibrosis and tubular atrophy, arteriolar hyalinosis, tubular microcalcifications, and global glomerulosclerosis [2]. Unfortunately, there are no specific molecular markers of CNIT, but it was recently experimentally shown that, e.g., the TWEAK/Fn14 pathway, is critically involved in the pathogenesis of CNIT [3]. Although it is known that overexposure to Tac causes CNIT trough level-dependently, even patients presenting with Tac trough levels within the therapeutic range (5–15 µg/L) are vulnerable to developing both acute or chronic CNIT [4,5,6,7,8,9].…”

MicroRNA-19a Targets Fibroblast Growth Factor-Inducible Molecule 14 and Prevents Tubular Damage in Septic AKI

“…Fn14 expression is relatively low in normal healthy tissues, while it could be rapidly activated in response to stress stimuli, which represents one of the main regulatory mechanisms for evoking inflammation or apoptosis. Activation of Fn14 by recombinant TWEAK (rTWEAK) mediates tubular damage and nephrotoxicity upon cyclosporin A (CsA) exposure [5]. Fn14 deficiency attenuates kidney IgG deposition, decreases inflammatory cell infiltration, and protects mice from developing lupus nephritis [6].…”

Genetic Variants Associated With Immunosuppressant Pharmacokinetics and Adverse Effects in the DeKAF Genomics Genome-wide Association Studies

“…4,5 Calcineurin inhibitor (CNI)-related nephrotoxicity occurs in up to 35% of recipients and it has been proposed that all recipients using CNIs eventually develop histological lesions consistent with toxicity in their allografts. 6 A review of 12 studies showed that the risk of CNI-related new onset diabetes after transplantation (NODAT) ranges from 2 to 50%. 7 Though there are several associated risk factors for NODAT, the biological basis is currently unknown.…”