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J. Biol. Chem., Vol. 278, Issue 36, 33951-33962, September 5, 2003

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High Glucose-suppressed Endothelin-1 Ca²⁺ Signaling via NADPH Oxidase and Diacylglycerol-sensitive Protein Kinase C Isozymes in Mesangial Cells^*

Hong Hua , Snezana Munk , Howard Goldberg ¶, I. George Fantus ¶ || and Catharine I. Whiteside  || **

From the Institute of Medical Science, ^||Banting and Best Diabetes Center, University Health Network, ^¶Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5S 1A8, Canada

High glucose (HG) is the underlying factor contributing to long term complications of diabetes mellitus. The molecular mechanisms transforming the glomerular mesangial cell phenotype to cause nephropathy including diacylglycerol-sensitive protein kinase C (PKC) are still being defined. Reactive oxygen species (ROS) have been postulated as a unifying mechanism for HG-induced complications. We hypothesized that in HG an interaction between ROS generation, from NADPH oxidase, and PKC suppresses mesangial Ca²⁺ signaling in response to endothelin-1 (ET-1). In primary rat mesangial cells, growth-arrested (48 h) in 5.6 mM (NG) or 30 mM (HG) glucose, the total cell peak [Ca²⁺]_i response to ET-1 (50 nM) was 630 ± 102 nM in NG and was reduced to 159 ± 15 nM in HG, measured by confocal imaging. Inhibition of PKC with phorbol ester down-regulation in HG normalized the ET-1-stimulated [Ca²⁺]_i response to 541 ± 74 nM. Conversely, an inhibitory peptide specific for PKC- did not alter Ca²⁺ signaling in HG. Furthermore, overexpression of conventional PKC- or novel PKC- in NG diminished the [Ca²⁺]_i response to ET-1, reflecting the condition observed in HG. Likewise, catalase or p47^phox antisense oligonucleotide normalized the [Ca²⁺]_i response to ET-1 in HG to 521 ± 58 nM and 514 ± 48 nM, respectively. Pretreatment with carbonyl cyanide m-chlorophenylhydrazone or rotenone did not restore Ca²⁺ signaling in HG. Detection of increased intracellular ROS in HG by dichlorofluorescein was inhibited by catalase, diphenyleneiodonium, or p47^phox antisense oligonucleotide. HG increased p47^phox mRNA by 1.7 ± 0.1-fold as measured by reverse transcriptase-PCR. In NG, H₂O₂ increased membrane-enriched PKC- and -, suggesting activation of these isozymes. HG-enhanced immunoreactivity of PKC- visualized by confocal imaging was attenuated by diphenyleneiodium chloride. Thus, mesangial cell [Ca²⁺]_i signaling in response to ET-1 in HG is attenuated through an interaction mechanism between NADPH oxidase ROS production and diacylglycerol-sensitive PKC.

Received for publication, March 19, 2003 , and in revised form, June 10, 2003.

^* This study was funded by the Canadian Institutes of Health Research and the Canadian Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Medical Sciences Bldg., Rm. 7302, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-946-7617; Fax: 416-946-5963; E-mail: catharine.whiteside{at}utoronto.ca.

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