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This Article Full Text Full Text (PDF) All Versions of this Article: 292/3/F1054    most recent 00286.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Zhang, W. Articles by Zhang, B.-X. Search for Related Content PubMed PubMed Citation Articles by Zhang, W. Articles by Zhang, B.-X.

Regulation of STIM1, store-operated Ca²⁺ influx, and nitric oxide generation by retinoic acid in rat mesangial cells

¹Geriatric Research, Education, and Clinical Center, South Texas Veterans Health Care System, Audie L. Murphy Division, and Departments of ²Biochemistry and ³Medicine, University of Texas Health Science Center San Antonio, San Antonio, Texas

Submitted 25 July 2006 ; accepted in final form 30 October 2006

It has been shown that store-operated Ca²⁺ influx (SOC) plays critical roles in the activation of endothelial nitric oxide (NO) synthase (eNOS) and generation of NO in endothelial cells. Recent studies indicate stromal interaction molecule 1 (STIM1) is the molecule responsible for SOC activation following Ca²⁺ depletion in the ER. Retinoic acids (RA) have beneficial effects in the treatment of renal diseases. The mechanism of the RA action is still largely unknown. In the current study, we used primary cultured rat mesangial cells to examine the effect of RA on SOC and STIM1. In these cells, BK caused concentration-dependent [Ca²⁺]_i mobilization. Treatment of the cells with RA, while it had no effect on the initial peak, reduced the plateau phase of BK-mediated [Ca²⁺]_i response, indicating the inhibition of SOC by RA. The level of STIM1 protein but not mRNA in RA-treated cells was significantly reduced. RA treatment did not affect TGF--mediated gradual Ca²⁺ influx which occurred by superoxide anion-mediated mechanism, indicating RA treatment specifically inhibited SOC in mesangial cells. RT-PCR and Western blot analysis demonstrated that eNOS was expressed in rat mesangial cells grown in media containing 11 and 30 but not 5.5 mM glucose. Downregulation of STIM1 protein and BK-induced SOC by RA treatment or STIM1 dsRNA were associated with abolished NO production. The 26S proteasome inhibitor lactacystin blocked the RA-mediated downregulation of BK-induced SOC, suggesting that ubiquitin-proteasome pathway may be involved in RA-mediated STIM1 protein downregulation in rat mesangial cells. Our data suggest that glucose-induced eNOS expression and NO production in mesangial cells may contribute to hyperfiltration in diabetes and RA may exert beneficial effects by downregulation of STIM1 and SOC in mesangial cells.

diabetes; protein downregulation; glomerular hyperfiltration; proteasome; lactacystin; eNOS

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