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Gq-dependent signaling upregulates COX2 in glomerular podocytes
Liming Wang1, Patrick J Flannery, Paul B Rosenberg
1Division of Nephrology, Department of Medicine, Duke University, Durham VA Medical Center, Durham, NC 27710, USA.
Journal of the American Society of Nephrology : JASN
|August 1, 2008
Summary
Gq signaling activates calcineurin, leading to increased cyclooxygenase 2 (COX2) expression and podocyte injury. Inhibiting COX2 can reduce prostaglandin E2 production and podocyte death, suggesting a therapeutic target.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Upregulation of cyclooxygenase 2 (COX2) in glomerular podocytes is linked to podocyte injury.
- Gq signaling pathways activate calcineurin, which mediates COX2 expression.
Purpose of the Study:
- To investigate the role of Gqalpha in promoting COX2 expression in podocytes.
- To elucidate the signaling cascade from Gqalpha to COX2 and subsequent podocyte injury.
Main Methods:
- Protein transduction of constitutively active Gq alpha subunit into immortalized podocytes.
- Measurement of inositol trisphosphate production, NFAT activation, and COX2 mRNA/protein levels.
- Assessment of prostaglandin E2 production, podocyte death, and COX2 expression in transgenic mouse models.
Main Results:
- Constitutively active Gqalpha stimulated COX2 mRNA and protein expression in podocytes.
- Increased COX2 levels correlated with elevated prostaglandin E2 production and podocyte death.
- COX2 inhibition attenuated prostaglandin E2 production and podocyte death.
- Podocyte-specific expression of active Gqalpha in transgenic mice enhanced COX2 levels in vivo.
Conclusions:
- Gq-dependent signaling activates calcineurin, upregulating COX2 expression.
- This pathway increases eicosanoid production and leads to podocyte injury.
- Targeting COX2 may offer a therapeutic strategy for podocyte-related kidney diseases.
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