Endothelial KLK8 Promotes Diabetic Nephropathy via a LIFR Dependent Mechanism.

Endothelial KLK8 is strongly upregulated in streptozotocin-induced diabetic mice and high-glucose–treated glomerular endothelial cells, and its loss improves albuminuria and glomerular pathology.

• Why it matters: Diabetic nephropathy involves unclear endothelial-cell pathways, and identifying KLK8-linked mechanisms could reveal actionable targets for disease progression.
• What they did: The study used global and endothelial-specific Klk8 knockout mice plus endothelial Klk8 knockdown in DBA/2J mice, alongside single-cell RNA sequencing, proteomics, and pathway testing; KLK8 cleavage of SDC4 and PLC/ERK/RUNX1-driven LIFR regulation were examined.
• The result: Lifr knockdown ameliorated DN hallmarks, improved endothelial-to-mesenchymal transition and SDC4 expression, and patient data showed KLK8 is positively correlated with LIF, soluble SDC4, and creatinine.

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