Regulation of cytokine-stimulated vascular cell adhesion molecule-1 expression in renal tubular epithelial cells.

Vascular cell adhesion molecule-1 (VCAM-1) is expressed not only by cytokine-activated endothelium in the kidney, but also by nonvascular cells such as renal tubular epithelial cells (TEC) and mesangial cells (MC). VCAM-1 is upregulated in these cells by the cytokines TNF-alpha, IL-1, and IFN-gamma. We have examined herein the regulation of VCAM-1 expression in TEC and the role played by protein kinase C (PKC). Activation of PKC with phorbol myristate acetate (PMA) or mezerein upregulates VCAM-1 expression by TEC dose-dependently. Maximal stimulation occurs after 6 hr, and declines thereafter. Activation of the protein kinase A pathway with forskolin does not upregulate VCAM-1. The TNF-alpha- and PMA-stimulated VCAM-1 expression is inhibited by the PKC and PKA inhibitor staurosporine (STS). The TNF-alpha-stimulated VCAM-1 expression is also inhibited by the PKC-specific inhibitor calphostin C. Protein synthesis inhibition with cycloheximide (CHX) and blocking of transcription with actinomycin D (ACT D) also inhibits the TNF-alpha and PMA-stimulated upregulation of VCAM-1. The TNF-alpha induced increase in VCAM-1 mRNA levels is blocked with STS and ACT D, but is superinduced with CHX. Thus, the TNF-alpha stimulated renal tubular VCAM-1 expression may involve activation of PKC and is transcriptionally regulated.