Nephrology Dialysis Transplantation, Vol 13, Issue 11 2814-2820, Copyright © 1998 by Oxford University Press
M Wu, C Yang, M Bens, H Yu, J Huang, C Wu, C Huang and A Vandewalle
Background: Nitric oxide (NO) has been shown to play a
role in cyclosporin (CsA) nephrotoxicity, but its mechanism of action is
still unclear. As inducible NO synthase (iNOS) mRNA
has been found to be expressed in rat medullary thick ascending limb (mTAL)
cells, we investigated the effects of CsA on NO production in a model of
mouse cultured mTAL cells. Materials and methods: The
experiments were carried out on sub-cultured cells derived from isolated
mTAL microdissected from the kidney of C57BL/6 mice. The identification of
the iNOS mRNA in mTAL microdissected segment and
cultured cell was confirmed by RT-PCR and RsaI
digestion. Nitrite (NO2-) released by mTAL cells was
determined using the modified Griess reagent method and taken as an index
of nitric oxide production. The cultured cells were treated with various
concentrations of CsA and different signal transduction regulators to
assess the effect and possible pathway(s) of action of CsA on NO production
in mTAL cells. Results: The basal production of NO by
mTAL cells increased by 1.8-fold following incubation with bacterial
lipopolysaccharide (LPS). Both aminoguanidine and
L-NAME inhibited NO production. CsA (10-300 ng/ml)
also inhibited NO production in a dose-dependent manner and prevented its
increase induced by LPS. Phorbol 12-myristate 13-acetate (PMA), a PKC
stimulator, enhanced slightly the production of NO under basal conditions
and prevented the inhibitory action of CsA on NO production. These results
suggest that the NO secreted by mouse cultured mTAL cells is dependent on
the PKC pathway. Conclusion: These results show that
CsA may downregulate the production of NO by cultured mTAL cells expressing
iNOS mRNA and that the PKC pathway is involved in this
process. Key words: cultured cells; cyclosporin;
kidney; nephrotoxicity; nitric oxide; thick ascending limbs
ORIGINAL ARTICLES
Cyclosporin inhibits nitric oxide production in medullary ascending limb cultured cells
Division of Nephrology, Chang Gung Memorial Hospital, 199 Twu Hwa North Road, Taipei, Taiwan; Institut de la Santé et de la Recherche Médicale U478, Faculté de Médecine Xavier Bichat, Institut Fédératif de Recherche 02, Paris, France; Corresponding author
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