Highlights
- •Advanced glycation endproducts (AGEs) degradation is significantly reduced in photoaged fibroblasts compared to non-photoaged fibroblasts.
- •The activity and expression of cathepsin D is significantly decreased in photoaged fibroblasts compared to non-photoaged fibroblasts.
- •Inhibiting Cathepsin D activity decreases AGEs degradation; whereas Cathepsin D overexpression significantly increases AGEs degradation.
- •AGEs accumulation in photo-damaged skin in vivo is inversely correlated with CatD expression.
- •Cathepsin D plays a major role in intracellular AGEs degradation, which may contribute to accelerated AGEs deposition in photoaged skin.
Abstract
Background
The deposition of advanced glycation end products (AGEs) is accelerated in photoaged
skin, but the underlying mechanisms remain elusive. Intracellular degradation has
been recently considered to play an important role in AGEs removal. Although lysosomal
cathepsin D (CatD), B (CatB), L(CatL) and proteasomes are found to degrade internalized
AGEs, it remains unknown which protease degrades internalized AGEs in human dermal
fibroblasts (HDFs), and whether a decrease in intracellular degradation contributes
to enhanced AGEs deposition in photoaged skin.
Objective
This study aims to investigate the specific proteases that contribute to intracellular
AGEs degradation in HDFs and regulate AGEs accumulation in photoaged skin.
Methods
Repetitive UVA irradiation was used to induce primary HDF photoaging in vitro. Uptake and degradation of AGE-BSA were verified and compared between photoaged and
non-photoaged fibroblasts with flow cytometry, ELISA and confocal microscopy. Proteasomal
and lysosomal activity, expression of CatD, CatB and CatL were also investigated between
photoaged and non-photoaged fibroblasts. Further, the effect of protease inhibitors
and CatD overexpression via lentiviral transduction on AGE-BSA degradation was analyzed.
Finally, the correlation between CatD expression and AGEs accumulation in sun-exposed
and sun-protected skin of people from different age was studied with immunohistochemistry.
Results
Fibroblasts underwent photoaging in vitro after repetitive UVA irradiation. AGE-BSA was taken up by both photoaged and non-photoaged
fibroblasts, but its degradation was significantly decreased in photoaged cells than
that of non-photoaged cells. Although the activity of proteasome, CatB, Cat L and
Cat D was significantly reduced in photoaged fibroblasts compared to that of non-photoaged
cells, and the expression of CatB, CatL and CatD was profoundly attenuated in photoaged
fibroblasts, inhibiting proteasome, CatB and CatL did not affect AGE-BSA degradation
in HDFs. In contrast, inhibiting CatD activity dose-dependently decreased AGE-BSA
degradation; whereas CatD overexpression significantly increased AGE-BSA degradation.
Importantly, AGEs accumulation in photo-damaged skin in vivo was inversely correlated
with CatD expression.
Conclusion
CatD plays a major role in intracellular AGEs degradation. Decreased CatD expression
and activity impairs intracellular AGEs degradation in photoaged fibroblasts, which
may contribute to accelerated AGEs deposition in photoaged skin. The present study
provides a potentially novel molecular basis for antiphotoaging therapy.
Keywords
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Article info
Publication history
Published online: February 19, 2018
Accepted:
February 14,
2018
Received in revised form:
January 1,
2018
Received:
May 14,
2017
Identification
Copyright
© 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
