Cathepsin K-dependent Angiopoietin processing in sepsis associated AKI

About This Grant

PROJECT SUMMARY BACKGROUND: Sepsis is the most common worldwide cause of death during hospitalization. One of the major complications contributing to death is sepsis-associated acute kidney injury (SA-AKI). Despite the rapid shutdown in kidney function, SA-AKI is associated with scant intrinsic cell death, suggesting the existence of mechanisms of physiological impairment that are at once non-lethal, but sufficiently robust to abrogate function. Vascular destabilization is one such target that we and many others have linked to SA-AKI and concomitant multi-organ dysfunction. How to measure and modulate the septic vasculature remain major gaps. We recently showed that the lysosomal cysteine protease cathepsin K (CTSK) is released by acutely inflamed macrophages and acts on key components of the vascular endothelial secretome. A newly reported CTSK target, Angiopoietin-2 (Angpt-2), is converted from a weak agonist to an antagonist of a receptor that signals vascular homeostasis, Tie2. When CTSK cleaves ANGPT2, the cleavage products of ANGPT2 strongly inhibit Tie2 signaling. Loss of Tie2 signaling switches the vascular endothelium to a hyperpermeable, pro-inflammatory, and pro-coagulant phenotype. In the setting of experimental systemic inflammation, CTSK activity rises a striking ~200-fold. Pharmacological cathepsin K inhibition ameliorates acute kidney injury (AKI), acute lung injury (ALI), and organismic survival during sterile inflammation and from polymicrobial sepsis. HYPOTHESIS: We will test the central hypothesis that macrophage-derived cathepsin K is an ANGPT- dependent mediator of SA-AKI. AIMS: Two parallel Aims are proposed. In Aim 1, we will study short and long-term kidney molecular, cellular, and physiological outcomes in murine models of sepsis examining gain of function variants of Angpt1 and Angpt2 and the role of the macrophage in suppling CTSK. In Aim 2, we will interrogate established cohorts to evaluate associations of peripheral CTSK and cleaved ANGPTs to short- and long-term outcomes following SA-AKI. CONCLUSIONS: No adjunctive therapy exists for SA-AKI, in part because current markers of sepsis are insufficiently mechanistic. Our preliminary results propose CTSK as a novel marker and mediator of SA-AKI acting through ANGPTs. Delineating a CTSK-ANGPT mechanistic pathway in septic organ failure offers powerful new translational opportunities for one of the world’s largest unmet medical needs.