Nephrology Dialysis Transplantation, Vol 13, Issue 4 911-918, Copyright © 1998 by Oxford University Press
I Hizoh, J Strater, C Schick, W Kubler and C Haller
Background: Radiocontrast-induced nephropathy is a
clinically important complication of invasive cardiological procedures. It
has been associated with DNA fragmentation of renal tubular cells, which is
a hallmark feature of programmed cell death (apoptosis). We investigated
the mechanism of this DNA fragmentation in an in vitro
model of radiocontrast cytotoxicity on renal epithelial cells.
Methods: Madin Darby canine kidney (MDCK) cell
monolayers were incubated (for 2-8 h) with isoiodine doses (27-111 mg
iodine/ml) of the highly hyperosmolal, ionic radiocontrast agent
diatrizoate or of the less hyperosmolal, non-ionic substance iopamidol.
Mannitol, urea, and NaCl control media of corresponding hyperosmolality
were used to evaluate the contribution of hypertonicity, hyperosmolality
and/or ionic strength to radiocontrast toxicity. DNA fragmentation was
assessed using fluorescence-activated cell sorting (FACS), agarose gel
electrophoresis and terminal deoxynucleotidyl transferase-mediated
deoxyuridine nick end labelling (TUNEL), cell morphology was analysed in
Giemsa-stained cytospins. Results: Diatrizoate induced
concentration- and time-dependent DNA fragmentation of MDCK cells which was
associated with morphological signs of apoptosis. Cycloheximide (1
&mgr;g/ml) did not prevent diatrizoate-induced DNA fragmentation,
indicating that it is not dependent on protein synthesis.
Diatrizoate-mediated cell death was associated with cell detachment from
the tissue culture matrix. However, the DNA fragmentation is not a
consequence of cell detachment since the prevention of cell attachment on
agarose-coated dishes induced significantly less DNA fragmentation than
diatrizoate. Iopamidol caused no detectable DNA breakdown. In contrast,
hypertonic mannitol and sodium chloride, but not hyperosmolal urea, induced
DNA fragmentation in MDCK cells, albeit less than diatrizoate.
Conclusions: The DNA fragmentation of MDCK cells
induced by diatrizioate is related to its hypertonicity in this
in vitro model of radiocontrast cytotoxicity. Nuclear
disintegration with subsequent cell death may contribute to the
pathophysiology of radiocontrast-induced nephropathy, particularly in the
hypertonic/hypoxic environment of the renal medulla. The present results
underscore the importance of avoiding hyperosmolal urine states in patients
at high risk of radiocontrast-induced nephropathy. Key
words: apoptosis; cytotoxicity; hypertonicity; MDCK;
radiocontrast; renal failure
ORIGINAL ARTICLES
Radiocontrast-induced DNA fragmentation of renal tubular cells in vitro: role of hypertonicity
Cardiovascular Center, Hayal Imre University of Health Sciences, Budapest, Hungary; Institute of Pathology, University of Ulm, Ulm, Germany; Department of Internal Medicine (Cardiology), University of Heidelberg, Bergheimer Strasse 58, D-69115 Heidelberg, Germany
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