What question did this study set out to answer?

To explore the role of cathepsin L in renal fibrosis associated with diabetic kidney disease.

June 7, 2026

1378-P: Tubular Cathepsin L Links Hyperglycemia to Renal Fibrosis and Represents a Druggable Target in Diabetic Kidney Disease

Key Points

To explore the role of cathepsin L in renal fibrosis associated with diabetic kidney disease.
Examined CTSL expression in human kidney specimens from DKD.
Utilized in vitro and in vivo models to study high glucose effects on CTSL regulation.
Implemented tubular epithelial-specific CTSL deletion in various renal fibrosis models.
CTSL was significantly increased in DKD kidneys, particularly in tubular epithelial cells.
High glucose stimulated CTSL maturation and activity, leading to renal fibrosis.
Inhibition of CTSL reduced fibrosis and improved kidney function in diabetic nephropathy models.

Abstract

Introduction and Objective: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, with progressive renal fibrosis driving irreversible renal decline. Current therapies inadequately target fibrotic mechanisms. Cathepsin L (CTSL), a hyperglycemia-induced lysosomal protease, has been implicated in tissue remodeling, but its mechanistic and translational relevance in DKD remains unclear. Methods: CTSL expression and localization were examined in human DKD kidney specimens. In vitro and in vivo models were used to investigate high-glucose-mediated regulation of CTSL maturation, trafficking, and activity. Functional effects of tubular CTSL were assessed using epithelial-fibroblast co-culture systems. Mice with tubular epithelial cell-specific deletion of CTSL were subjected to multiple renal fibrosis models. Translational studies were performed using an orally bioavailable, internally developed CTSL inhibitor in db/db mice. Results: CTSL was markedly upregulated in human DKD kidneys, with selective enrichment in tubular epithelial cells. High glucose enhanced CTSL maturation and enzymatic activity via increased mannose-6-phosphate glycosylation and lysosomal trafficking. Functionally, tubular CTSL induced epithelial-mesenchymal transition and promoted paracrine fibroblast-to-myofibroblast activation, driving extracellular matrix accumulation. Tubular CTSL deletion attenuated renal fibrosis across unilateral ureteral obstruction, ischemia-reperfusion injury, and diabetic nephropathy models. Treatment with the internally developed CTSL inhibitor reduced fibrotic burden and improved renal and metabolic parameters in db/db mice. Conclusion: Tubular epithelial CTSL is a metabolically regulated driver of renal fibrosis in DKD. Genetic ablation and pharmacologic inhibition using an internally developed CTSL inhibitor confer robust renoprotection, supporting CTSL as a translatable antifibrotic target. Disclosure M. Zhao: None. X. Li: None. M. Li: None. X. Yan: None. J. Yang: None. Funding National Natural Science Foundation of China (82300917, 82570960, 82341076)

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