Nephrol Dial Transplant (1999) 14: 2130-2136
© 1999 European Renal Association-European Dialysis and Transplant Association
Regulation of hyaluronan-stimulated VCAM-1 expression in murine renal tubular epithelial cells
1 Physiological Institute, University of Zürich-Irchel and 2 Division of Nephrology, Department of Medicine, University Hospital, Zürich, Switzerland
Correspondence and offprint requests to: Rudolf P. Wüthrich, Division of Nephrology, University Hospital, Rämistrasse 100, CH-8091 Zürich, Switzerland.
Background. Cytokines stimulate the expression of the adhesion molecule VCAM-1 in renal tubular epithelial cells. We have recently shown that VCAM-1 can also be upregulated by low molecular weight breakdown products of the matrix constituent hyaluronan (HA) (J Immunol 1998; 161: 3431–3437). The mechanisms of VCAM-1 expression in response to HA remain to be defined.
Methods. Using a defined mouse cortical tubular (MCT) cell line we investigated the effect of protein kinase C (PKC) and tyrosine kinase (TK) inhibition on the HA-stimulated VCAM-1 expression by cell ELISA and RT–PCR or Northern blotting. Furthermore, we examined the effect of PKC and TK inhibition on NF-
B.
Results. We found that the PKC inhibitor GF109203X (acting on conventional, novel and atypical isoforms) inhibited the HA-stimulated VCAM-1 expression in MCT cells dose-dependently up to 90%, whereas chelerythrine (acting on conventional and novel isoforms) had no effect. Downregulation of PKC with PMA did not prevent the HA-stimulated VCAM-1 expression, suggesting that Ca2+- and diacylglycerol-independent (atypical) isoforms of PKC are involved. The TK inhibitor genistein also inhibited the HA-stimulated VCAM-1 expression at the mRNA and protein level up to 70%. Interestingly, the HA-stimulated nuclear translocation of NF-B could not be prevented with GF109203X and genistein.
Conclusion. These data demonstrate that the HA-stimulated VCAM-1 expression in MCT cells involves PKC and TK pathways. The absence of an effect of PKC and TK inhibitors on the nuclear translocation of NF-B suggests that additional transcription factors are involved for VCAM-1 expression.
Keywords: hyaluronan; ICAM-1; protein kinase C; tyrosine kinase; VCAM-1
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