ABSTRACT Aging accelerates renal fibrosis driven by renal tubular epithelial cells (RTECs) senescence. However, the underlying molecular mechanisms remain elusive. We demonstrate that lysosomal transmembrane protein 5 (LAPTM5) is markedly upregulated in aged kidney models and correlates with renal senescence and fibrosis severity. Mechanistically, LAPTM5 drives RTECs epithelial‐mesenchymal transition (EMT) by interacting with USP10 and facilitating its lysosomal degradation, thereby relieving PTEN‐mediated inhibition of the PI3K/AKT/mTOR‐mediated autophagy pathway. This accelerates kidney fibrosis. Functionally, PTEN overexpression rescues LAPTM5‐induced EMT in RTECs, while the PTEN agonist sophocarpine ameliorates renal fibrosis and preserves function in D‐galactose‐induced progeroid mice by restoring autophagy. Our findings identify the LAPTM5‐USP10‐PTEN axis as a critical regulator of autophagy‐mediated renal fibrosis in aging kidney.
Wang et al. (Mon,) studied this question.
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