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

Claus, Meike; Herro, Rana; Wolf, Dennis; Buscher, Konrad; Rudloff, Stefan; Huynh-Do, Uyen; Burkly, Linda; Croft, Michael; Sidler, Daniel (2018). The TWEAK/Fn14 pathway is required for calcineurin inhibitor toxicity of the kidneys. American journal of transplantation, 18(7), pp. 1636-1645. Wiley-Blackwell 10.1111/ajt.14632

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension

UniBE Contributor:

Rudloff, Stefan and Huynh-Do, Uyen

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1600-6135

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Uyen Huynh-Do

Date Deposited:

01 Oct 2019 12:44

Last Modified:

24 Oct 2019 09:20

Publisher DOI:

10.1111/ajt.14632

PubMed ID:

29266762

Uncontrolled Keywords:

animal models basic (laboratory) research/science fibrosis immunosuppressant - calcineurin inhibitor (CNI) interstitial fibrosis and tubular atrophy kidney (allograft) function/dysfunction kidney transplantation/nephrology pharmacology translational research/science

BORIS DOI:

10.7892/boris.131740

URI:

https://boris.unibe.ch/id/eprint/131740

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