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Am J Physiol Renal Physiol 282: F151-F163, 2002. First published August 15, 2001; doi:10.1152/ajprenal.0055.2001
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Vol. 282, Issue 1, F151-F163, January 2002

Mesangial cell filamentous actin disassembly and hypocontractility in high glucose are mediated by PKC-zeta

John A. Dlugosz, Snezana Munk, Eric Ispanovic, Howard J. Goldberg, and Catharine I. Whiteside

Institute of Medical Science and Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8

In high glucose (HG), mesangial cells (MCs) lose their contractile response to endothelin-1 (ET-1) coincidently with filamentous (F)-actin disassembly. We postulated that these MC phenotypic changes are mediated by altered protein kinase C (PKC) isozyme activity, myosin light chain (MLC20) phosphorylation, or Ca2+ signaling. MCs were growth arrested for 24 h in 0.5% fetal bovine serum (FBS)-DMEM in 5.6 (normal glucose; NG) or 30 mM glucose (high glucose; HG). In HG, the planar area was reduced [2,608 ± 135 vs. 3,952 ± 225 (SE) µm2 in NG, P < 0.01, n = 31] with no contractile response to 0.1 µM ET-1. Mannitol did not affect cell size or ET-1 response. Confocal imaging of fluo 3- loaded cells revealed that the peak intensity of ET-1-induced Ca2+ signaling was not altered in HG vs. NG. Immunoblotting of phosphorylated MLC20 showed that HG increased mono- and decreased unphosphorylated MLC20 (42 ± 16 and 49 ± 15 vs. 13 ± 3 and 80 ± 4% of total in NG, P < 0.05, n = 3), but the peak phosphorylation responses to ET-1 were identical in NG and HG. ET-1 stimulated translocation of PKC-delta and -epsilon from cytosolic to membrane and particulate fractions identically in NG and HG but did not cause PKC-zeta translocation. In HG, membrane accumulation of PKC-zeta was observed. Membrane PKC-zeta activity measured by immunoprecipitation and 32P phosphorylation of PKC-epsilon pseudosubstrate peptide was 190 ± 18% of NG (P < 0.01, n = 4), which was completely inhibited by pretreatment with a myristoylated peptide inhibitor (ZI). In HG, pretreatment with ZI for 24 h restored normal MC size and contractile and F-actin disassembly responses to ET-1. In conclusion, in HG, decreased MC size is due to decreased F-actin assembly, and loss of contractile response to ET-1 occurs in the presence of normal Ca2+ signaling and normal MLC20 phosphorylation. In HG, altered F-actin and contractile functions in MCs are mediated by PKC-zeta .

endothelin-1; calcium signaling; myosin light chain phosphorylation; protein kinase C-zeta


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