Mice, double deficient in lysosomal serine carboxypeptidases Scpep1 and Cathepsin A develop the hyperproliferative vesicular corneal dystrophy and hypertrophic skin thickenings

• Published in: PloS one Vol. 12; no. 2; p. e0172854
• Main Authors: Pan, Xuefang, Wang, Yanting, Lübke, Torben, Hinek, Aleksander, Pshezhetsky, Alexey V
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.02.2017; Public Library of Science (PLoS)
• Subjects: AKT protein; Animal tissues; Animals; Antibiotics; Aqueous Humor - metabolism; Autophagy; Bioaccumulation; Biochemistry; Biology and Life Sciences; Carboxypeptidase; Carboxypeptidase A; Carboxypeptidase C; Carboxypeptidases - genetics; Carboxypeptidases - metabolism; Cathepsin A - genetics; Cathepsin A - metabolism; Cathepsins; Cell Proliferation; Computational fluid dynamics; Cornea; Corneal diseases; Corneal Dystrophies, Hereditary - genetics; Corneal Dystrophies, Hereditary - metabolism; Corneal dystrophy; Dystrophy; Endothelin; Endothelin 1; Endothelin-1 - pharmacology; Endothelium; Epidermis; Epidermis - pathology; Epithelial cells; Eutrophication; Extracellular signal-regulated kinase; Female; Fibroblasts; Fibroblasts - cytology; Fibrosis; Genetic aspects; Glaucoma; Hemodynamics; Hospitals; Hypertension; Kinases; Laboratories; Lysosomes - enzymology; Male; Medicine and Health Sciences; Mice; Mice, Knockout; Muscles; Myocytes, Smooth Muscle - cytology; Myofibroblasts - cytology; Phosphorylation; Physiological aspects; Physiology; Research and Analysis Methods; Risk factors; Rodents; Serine; Serine carboxypeptidase; Skin; Skin - pathology; Smooth muscle; Thickening; Vasoactive agents; Canada; Ontario Canada; Montreal Quebec Canada; Quebec Canada
• DOI: 10.1371/journal.pone.0172854
• ISSN: 1932-6203

Vasoactive and mitogenic peptide, endothelin-1 (ET-1) plays an important role in physiology of the ocular tissues by regulating the growth of corneal epithelial cells and maintaining the hemodynamics of intraocular fluids. We have previously established that ET-1 can be degraded in vivo by two lysosomal/secreted serine carboxypeptidases, Cathepsin A (CathA) and Serine Carboxypeptidase 1 (Scpep1) and that gene-targeted CathAS190A /Scpep1-/- mice, deficient in CathA and Scpep1 have a prolonged half-life of circulating ET-1 associated with systemic hypertension. In the current work we report that starting from 6 months of age, ~43% of CathAS190A /Scpep1-/- mice developed corneal clouding that eventually caused vision impairment. Histological evaluation of these mice demonstrated a selective fibrotic thickening and vacuolization of the corneas, resembling human hyperproliferative vesicular corneal stromal dystrophy and coexisting with a peculiar thickening of the skin epidermis. Moreover, we found that cultured corneal epithelial cells, skin fibroblasts and vascular smooth muscle cells derived from CathA/Scpep1-deficient mice, demonstrated a significantly higher proliferative response to treatment with exogenous ET-1, as compared with cells from wild type mice. We also detected increased activation level of ERK1/2 and AKT kinases involved in cell proliferation in the ET-1-treated cultured cells from CathA/Scpep1 deficient mice. Together, results from our experimental model suggest that; in normal tissues the tandem of serine carboxypeptidases, Scpep1 and CathA likely constitutes an important part of the physiological mechanism responsible for the balanced elimination of heightened levels of ET-1 that otherwise would accumulate in tissues and consequently contribute to development of the hyper-proliferative corneal dystrophy and abnormal skin thickening.