Macrophages are important mediators of inflammation. Our data show stanniocalcin-1 (STC1) decreases macrophage response to chemoattractants and migration across an endothelial monolayer. STC1 also diminishes superoxide generation in macrophages, by inducing uncoupling protein-2 (UCP2), and inhibits the NF-?B pathway. In cultured endothelial cells, STC1 inhibits cytokine-induced changes in permeability and tight junction protein expression. STC1 transgenic mice, which exhibit elevated serum levels and preferential expression of STC1 in macrophages and endothelium, display less inflammatory macrophages in the glomeruli during anti-glomerular basement membrane (GBM) disease, resulting in kidney protection. Overall hypothesis: STC1 suppresses inflammation through inhibition of macrophage recruitment and function, and cytokine-induced increase in endothelial permeability.
In Specific Aim I, we will determine mechanisms of UCP2 upregulation by STC1 and the role of superoxide in STC1-mediated inhibition of NF-?B in macrophages.
In Specific Aim II, we will determine the effect of STC1 on cytokine-induced changes in expression and assembly of tight junction proteins in cultured primary kidney endothelial cells.
In Specific Aim III, in the context of anti-GBM disease, we will examine endothelial permeability of native kidney vessels, as well as kidney inflammation and function, after kidney endothelium-specific or macrophage-specific overexpression or deletion of STC1.

Public Health Relevance

Our preliminary results show stanniocalcin-1 protein inhibits macrophages, stabilizes blood vessels and decreases kidney inflammation. We plan to study how stanniocalcin-1 inhibits macrophages and how it stabilizes blood vessels during inflammation. This is important because available conventional therapies for inflammation are frequently associated with significant side effects, and our proposed experiments could lead to identification of new medications to treat inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080306-05
Application #
8515390
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Flessner, Michael Francis
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$315,766
Indirect Cost
$110,055
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Sheikh-Hamad, David (2010) Mammalian stanniocalcin-1 activates mitochondrial antioxidant pathways: new paradigms for regulation of macrophages and endothelium. Am J Physiol Renal Physiol 298:F248-54

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