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Live kidney slices present a novel method for delineating the mechanisms of calcineurin inhibitor‐mediated nephrotoxicity
Author(s) -
Kelly Mark,
Crawford Carol,
Loo RueyLeng,
Delaney Michael,
Farmer Chris,
Wildman Scott S.P.,
PeppiattWildman Claire. M.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.646.8
Subject(s) - calcineurin , nephrotoxicity , vasoconstriction , kidney , tacrolimus , medicine , pharmacology , vasodilation , transplantation , urology , kidney transplantation , renal function
Cyclosporin A (CsA) and Tacrolimus (FK‐506) are potent immunosuppressant drugs widely used to prevent allograft rejection in organ transplantation. They are calcineurin inhibitors (CNIs) and have limiting side effects including nephrotoxicity that impact upon long‐term renal allograft and patient survival in other organ transplantation. The precise mechanisms of CNI‐induced toxicity are unknown, although ischemic injury resulting from impairment of endothelial cell function, reduced production of endogenous renal vasodilators and concomitant release of vasoconstrictors resulting in net vasoconstriction have been described. We have utilized the live kidney slice model, developed by our group [1], to investigate the mechanisms of CNI‐induced nephrotoxicity in the renal medulla, a region of the kidney that is particularly sensitive to ischemia Data presented here demonstrates both CsA (600 ng/ml) and FK‐506 (800 ng/ml) cause vasoconstriction (9.9% ± 0.88% and 9.2% ± 0.63%, respectively) of vasa recta via their specific action at contractile pericytes. Tubule diameter was unaffected by bath application of both CsA and FK‐506. Data suggest that CNI‐induced constriction of vasa recta by pericytes may exacerbate renal medullary ischemia contributing to observed nephrotoxicity in solid organ transplantation. Research supported by the Medical Research Council and University of Kent.