S-40-6: activation of cathepsin s/cxcl1 axis-mediated macrophage and tubular cell crosstalk leads to renal inflammation and fibrosis

Chronic kidney disease (CKD) is a progressive and irreversible pathological feature with no effective therapies in clinic. Persistent inflammation is a key characteristic of CKD that leads to progressive renal fibrosis. Cathepsin S (Cat S) is a cysteine protease contributing to the progression of multiple diseases through modulating inflammation, but its role in the pathogenesis of CKD remains unknown. Here, we found that Cat S was significantly upregulated in renal macrophage during unilateral ureteral obstruction (UUO). Knockout of Cat S attenuated, whereas AAV (adeno-associated virus)-mediated macrophage-specific overexpression of Cat S exacerbated macrophage recruitment, inflammatory factors expression, renal injury and epithelial mesenchymal transition (EMT). Using macrophage depletion, bone marrow transplantation, protein chip and luciferase reporter assays, we determined that macrophage-derived Cat S induced CXCL1 secretion from tubular cells which mediated macrophage recruitment. Immunoprecipitation combined with mass spectrometry identified that Cat S directly bind with Rack1, which disrupted the Rack1-IKK-alpha complex to activate NF-kappaB signaling. Knockdown of CXCL1 attenuated aggravating pathological changes in macrophage-specific overexpression of Cat S mice. Furthermore, therapeutic administration of Cat S inhibitor significantly reversed renal injury in UUO mice. In patients with renal tubulointerstitial lesions, increase expression of plasma and renal Cat S was associated with renal function impairment and fibrosis severity. Our study demonstrated that Cathepsin S/CXCL1 axis mediated interaction between macrophage and tubular cell that contributed to CKD, with translational implications in humans.