Cellular activation of mesangial gelatinase A by cytochalasin D is accompanied by enhanced mRNA expression of both gelatinase A and its membrane-associated gelatinase A activator (MT-MMP)

摘要

pActivation of gelatinase A represents a crucial regulatory step in the control of its enzymic activity. Rat kidney mesangial cells secrete predominantly latent gelatinase A that can be activated following treatment with cytochalasin D. In the present paper we provide new evidence, using reverse transcription-PCR, that treatment of rat mesangial cells with cytochalasin D enhances the steady-state level of mRNA of the membrane-type matrix metalloproteinase (MT-MMP), as well as of gelatinase A, with no change in the level of tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA. Since the TIMP-2 protein level is reduced in conditioned medium from cytochalasin D-treated cells, the results of the present study are consistent with a model in which the action of cytochalasin D is to cause extracellular gelatinase A and TIMP-2 to be sequestered at the plasma membrane, forming a heterotrimeric complex with MT-MMP. In this manner, TIMP-2 may assume a bifunctional role causing: (i) inhibition of gelatinase A in the extracellular compartment; and (ii) guiding gelatinase A to activation through a membrane association with MT-MMP./p