Cathepsin K-dependent Angiopoietin processing in sepsis associated AKI
openNIDDK - National Institute of Diabetes and Digestive and Kidney Diseases
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.
Up to $823K
health research