Mammalian stanniocalcin-1 activates mitochondrial antioxidant pathways: new paradigms for regulation of macrophages and endothelium

Abstract

The mammalian homolog of the fish calcium regulatory hormone stanniocalcin-1 (STC1) is ubiquitously expressed and likely functions in an autocrine/paracrine fashion. Mammalian STC1 does not appear to exert significant effects on serum calcium, and its physiological role remains to be determined. In macrophages, STC1 decreases intracellular calcium and cell mobility; attenuates the response to chemoattractants; and diminishes superoxide generation through induction of uncoupling protein-2 (UCP2). In cytokine-treated endothelial cells, STC1 attenuates superoxide generation and the activation of inflammatory pathways [c-Jun NH(2)-terminal kinase (JNK) and NF-kappaB]; maintains the expression of tight junction proteins, preserving the endothelial monolayer seal; and decreases transendothelial migration of leukocytes. Combined, the effects of STC1 on endothelial cells and macrophages predict potent anti-inflammatory action. Indeed, application of the anti-glomerular basement membrane (GBM) glomerulonephritis model to STC1 transgenic mice that display increased expression of STC1 transgene in endothelial cells and macrophages yields renal protection. Our data suggest that STC1 activates antioxidant pathways in endothelial cells and macrophages and displays cytoprotective and anti-inflammatory actions.

Fig. 1.

Mitochondrial uncoupling decreases ATP and superoxide generation. Transfer of electrons (e⁻) from high-energy molecules (NADH and FADH₂) by complexes of the respiratory chain (I–IV) generates H⁺ ion gradient (pH difference) between the matrix and the intermembrane space, while producing superoxide (O₂⁻). Hydrogen ion gradient is utilized by the ATP synthase to generate ATP. Alternatively, H⁺ ion gradient may be dissipated by uncoupling proteins such as uncoupling protein (UCP)2, bypassing ATP synthase; this diminishes ATP synthesis and superoxide generation. NAD, nicotinamide adenine dinucleotide.

Fig. 2.

Proposed scheme for stanniocalcin-1 (STC1) action in endothelial cells. TNF-α activates NF-κB (increased IκB phosphorylation) and increases free radical production [reactive oxygen species (ROS)]. Activities of NF-κB and c-Jun NH₂-terminal kinase (JNK) pathways are redox sensitive. STC1 diminishes free radical production (increasing GSH/GSSG), providing a mechanism for downregulation of NF-κB and JNK.