Format

Send to

Choose Destination
Redox Biol. 2018 Apr;14:88-99. doi: 10.1016/j.redox.2017.08.019. Epub 2017 Sep 1.

Role of glutathione biosynthesis in endothelial dysfunction and fibrosis.

Author information

1
Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa", (CSIC-UAM), Madrid, Spain.
2
Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de Madrid and Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), Spain.
3
Department of Pathology, Instituto de Investigaciones Sanitarias-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spain.
4
Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa", (CSIC-UAM), Madrid, Spain. Electronic address: slamas@cbm.csic.es.

Abstract

Glutathione (GSH) biosynthesis is essential for cellular redox homeostasis and antioxidant defense. The rate-limiting step requires glutamate-cysteine ligase (GCL), which is composed of the catalytic (GCLc) and the modulatory (GCLm) subunits. To evaluate the contribution of GCLc to endothelial function we generated an endothelial-specific Gclc haplo-insufficient mouse model (Gclc e/+ mice). In murine lung endothelial cells (MLEC) derived from these mice we observed a 50% reduction in GCLc levels compared to lung fibroblasts from the same mice. MLEC obtained from haplo-insufficient mice showed significant reduction in GSH levels as well as increased basal and stimulated ROS levels, reduced phosphorylation of eNOS (Ser 1177) and increased eNOS S-glutathionylation, compared to MLEC from wild type (WT) mice. Studies in mesenteric arteries demonstrated impaired endothelium-dependent vasodilation in Gclc(e/+) male mice, which was corrected by pre-incubation with GSH-ethyl-ester and BH4. To study the contribution of endothelial GSH synthesis to renal fibrosis we employed the unilateral ureteral obstruction model in WT and Gclc(e/+) mice. We observed that obstructed kidneys from Gclc(e/+) mice exhibited increased deposition of fibrotic markers and reduced Nrf2 levels. We conclude that the preservation of endothelial GSH biosynthesis is not only critical for endothelial function but also in anti-fibrotic responses.

KEYWORDS:

Endothelial dysfunction; Glutamate-cysteine ligase; Glutathione; Kidney Fibrosis; ROS

PMID:
28888203
PMCID:
PMC5596265
DOI:
10.1016/j.redox.2017.08.019
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center