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Abstract: FR-PO1008

Investigating Lysozyme as a Mediator of Tubular Epithelial Inflammation: An Example of CKD Knowledge Graph Target Discovery and Validation

Session Information

  • CKD: Pathobiology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms


  • Woollard, Kevin, AstraZeneca, Cambridge, United Kingdom
  • Musial, Barbara, AstraZeneca, Cambridge, United Kingdom
  • Nilsson, Karolina A., AstraZeneca, Cambridge, United Kingdom
  • Liarte Marin, Elena, AstraZeneca, Cambridge, United Kingdom
  • Buvall, Lisa, AstraZeneca, Cambridge, United Kingdom
  • MacPhee, Iain, AstraZeneca, Cambridge, United Kingdom
  • Ryaboshapkina, Maria, AstraZeneca, Cambridge, United Kingdom
  • Kirik, Ufuk, AstraZeneca, Cambridge, United Kingdom
  • Paul, Dirk S., AstraZeneca, Cambridge, United Kingdom
  • Bohlooly, Mohammad, AstraZeneca, Cambridge, United Kingdom
  • Taddei, Andrea, BenevolentAI, London, United Kingdom
  • Rolando, Delphine M. Y., BenevolentAI, London, United Kingdom
  • Mori, Andres, BenevolentAI, London, United Kingdom
  • Bendtsen, Claus, AstraZeneca, Cambridge, United Kingdom
  • Laerkegaard Hansen, Pernille B., AstraZeneca, Cambridge, United Kingdom

Lysozyme (Lyz) is an antimicrobial enzyme catalysing hydrolysis of bacterial cell walls. Lyz was identified as a potential target for CKD by applying an AI-driven drug discovery approach to a Knowledge Graph. Clinical evidence included nephropathy of chronic myelomonocytic leukaemia associated with increased circulating levels of Lyz with tubular kidney staining. Orthogonal genetic support from Mendelian mutations as cause for renal amyloidosis, and common variants in LYZ associated with increased monocyte counts, associated with systemic inflammation and cardiovascular risk in CKD. Published data shows circulating levels of Lyz is associated with decline in renal function and predict worse CKD survival. Therefore, we wanted to investigate if Lyz is a mediator of kidney injury using in-vitro models of tubular inflammation using proximal tubular epithelial cells (PTEC).


Primary PTEC were cultured with human Lyz at physiological concentrations (0-50ug/ml) over 0-30mins-7hrs-2days. We measured markers of PTEC injury, inflammation, ROS, ER stress, MAPK signalling and viability.


Overall while we saw a dose dependent increase in KIM-1/clusterin, there was very limited or no change in cytokines (IL8, IL1b, TNFa, IL6), ROS, ER stress, MAPK phosphorylation or cell death after Lyz treatment at all time points. We confirmed PTEC intracellular Lyz uptake using in-direct fluorescence assays. We examined Lyz expression directly from PTEC or primary macrophages in response to CKD inflammatory triggers. We could not detect any expression from PTEC, but potent secretion from macrophages. Therefore, we tested PTEC:macrophage co-culture. Like Lyz incubation alone, activated macrophages secreting lysozyme did not overtly lead to PTEC inflammation.


Our data show that Lyz has limited effect on PTEC inflammation in-vitro. These observations may indicate that elevated Lyz seen in CKD patients could be a marker of disease or of systemic inflammation in CKD. However, in-vivo data would be needed to draw firm conclusions on the relationship between long-lasting chronic exposure to elevated Lyz levels and tubular damage in CKD patients.


  • Commercial Support – AstraZeneca