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Am J Physiol Renal Physiol (August 15, 2001). doi:10.1152/ajprenal.0055.2001
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Articles in PresS, published online ahead of print August 15, 2001
Am J Physiol Renal Physiol, 10.1152/ajprenal.0055.2001
Submitted on February 23, 2001
Accepted on August 2, 2001

Mesangial Cell Filamentous-Actin Disassembly and Hypocontractility in High Glucose Are Mediated by Protein Kinase C-{zeta}

John A Dlugosz1*, Snezana Munk1, Eric Ispanovic1, Howard J Goldberg1, and Catharine I Whiteside1

1 Institute of Medical Science, University of Toronto, Toronto, ON, Canada

* To whom correspondence should be addressed. E-mail: john.dlugosz{at}utoronto.ca.

In high glucose (HG), mesangial cells (MCs) lose their contractile response to endothelin-1 (ET-1) coincident 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% FBS DMEM in 5.6 mM normal glucose (NG) or 30 mM HG. In HG, planar area was reduced (2608 ± 135 µm2 vs 3952 ± 225 µm2 in NG, mean ± SEM, 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 intensity of ET-1-induced Ca2+ signaling was not altered in HG vs NG. Immunoblotting of phosphorylated MLC20 showed that HG increaed mono- and decreased un-phosphorylated MLC20 (42 ± 16% and 49 ± 15% of total, vs 13 ± 3% and 80 ± 4% of total in NG, p < 0.05, n=3) but the peak phosphorylation responses to ET-1 are identical in NG and HG. ET-1-stimulated translocation from cytosol to membrane and particulate fractions of PKC-{delta} and -{epsilon} 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 to normal MC size and the 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, MC altered cytoskeletal and contractile functions are mediated by PKC-{zeta}.




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