LAPTM5 Promotes Age-Related Renal Fibrosis via USP10/PTEN-Mediated Autophagy Inhibition

Area of Science:

• Nephrology
• Cellular senescence
• Molecular mechanisms of aging

Background:

• Aging is a major risk factor for chronic kidney disease, characterized by renal fibrosis.
• Renal tubular epithelial cells (RTECs) senescence contributes significantly to age-related kidney fibrosis.
• The precise molecular drivers of RTEC senescence and fibrosis during aging are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying age-accelerated renal fibrosis.
• To investigate the role of lysosomal transmembrane protein 5 (LAPTM5) in RTEC senescence and kidney fibrosis.
• To identify potential therapeutic targets for mitigating age-related renal fibrosis.

Main Methods:

• Analysis of LAPTM5 expression in aged kidney models.
• Investigation of LAPTM5's interaction with USP10 and its effect on PTEN.
• Assessment of the PI3K/AKT/mTOR/autophagy pathway modulation by LAPTM5.
• Functional studies involving PTEN overexpression and the PTEN agonist sophocarpine in cellular and mouse models.

Main Results:

• LAPTM5 is upregulated in aged kidneys and correlates with senescence and fibrosis.
• LAPTM5 promotes RTEC epithelial-mesenchymal transition (EMT) by degrading USP10, which relieves PTEN inhibition of autophagy.
• PTEN restoration or activation ameliorates LAPTM5-induced EMT and reduces renal fibrosis in vivo.
• The LAPTM5-USP10-PTEN axis critically regulates autophagy in aging-related kidney fibrosis.

Conclusions:

• The LAPTM5-USP10-PTEN axis is a key regulator of autophagy in age-related renal fibrosis.
• Targeting this pathway, for instance with PTEN agonists like sophocarpine, may offer a therapeutic strategy for aging kidneys.
• Understanding this mechanism provides new insights into the cellular basis of kidney aging and fibrosis.