Mice, double deficient in lysosomal serine carboxypeptidases Scpep 1 and Cathepsin A develop the hyperproliferative vesicular corneal dystrophy and hypertrophic skin thickenings
Authors
Xuefang Pan, Yanting Wang, Torben LuÈbke, Aleksander Hinek, Alexey V. Pshezhetsky
Institution
University of Montreal
Country
Canada
Year
2017
Journal
PLOS One
Abstract
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 Cath-
AS190A /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.