Abstract: FR-PO1181
Absence of Lymphoid Cells May Aggravate Macrophage-Mediated Kidney Injury but Improve Repair in Immunodeficient Mouse Model of Adenine-Induced CKD
Session Information
- CKD: Mechanisms - 2
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Petrillo, Federica, AstraZeneca R&D Cambridge, Cambridge, Cambridgeshire, United Kingdom
- Mulay, Shrikant R., AstraZeneca R&D Cambridge, Cambridge, Cambridgeshire, United Kingdom
- Woollard, Kevin, AstraZeneca R&D Cambridge, Cambridge, Cambridgeshire, United Kingdom
- Miller, Lorraine, AstraZeneca R&D Cambridge, Cambridge, Cambridgeshire, United Kingdom
- Tesan Tomic, Tajana, AstraZeneca R&D Gothenburg, Molndal, Västra Götaland, Sweden
- Soderberg, Magnus, AstraZeneca R&D Gothenburg, Molndal, Västra Götaland, Sweden
- Thomas, Aurelie, AstraZeneca R&D Cambridge, Cambridge, Cambridgeshire, United Kingdom
- Laerkegaard Hansen, Pernille B., AstraZeneca R&D Gothenburg, Molndal, Västra Götaland, Sweden
- Dearman, Matthew S., AstraZeneca R&D Cambridge, Cambridge, Cambridgeshire, United Kingdom
- Ling, Stephanie, AstraZeneca R&D Cambridge, Cambridge, Cambridgeshire, United Kingdom
Group or Team Name
- Early CVRM Renal Bioscience, AstraZeneca R&D.
Background
Myeloid and lymphoid subpopulations have shown to be both protective and mediators of kidney injury. Mechanisms of crosstalk between pro- and anti-inflammatory actions of these effector cells is still unclear.
Methods
NSG mice (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ) are deficient in mature lymphocytes, in natural killer cell cytotoxic activity and in cytokine signalling. In the current study we established a novel NSG mouse model of kidney injury by inducing renal failure through dietary delivery of 0.15% adenine for 7 days, compared to C57BL/6N mice and examined response to recovery by removing adenine diet for 14 days. We used Image Mass Cytometry to label 34 markers of immune cell kidney network and kidney injury pattern in adenine versus controls in NSG mice.
Results
CKD was induced in NSG and C57BL/6N mice by feeding 0.15% adenine diet. NSG-CKD mice showed 12% and 17% weight-loss (WL) after 3 and 6 days, respectively, while C57BL/6N-CKD mice showed 10% WL after 7 days. Blood Urea Nitrogen (BUN) and plasma Creatinine were increased 2-fold in NSG-CKD than C57BL/6N-CKD mice with a considerable amount of urinary excreted kidney injury markers, KIM-1 and NGAL after 4 days of treatment. NSG-CKD mice showed downregulation of epithelial markers (Megalin, SGLT2, GLUT-1, NKCC2, E-Cadherin) and upregulated markers of fibrosis (αSMA, Collagen I, Vimentin) that was not seen in C57BL/6N-CKD mice. Immune profile of NSG-CKD mice revealed increased macrophage-based inflammation with upregulated F4/80, CD45, CD11b, CD206, and loss of innate and adaptive lymphocytes immune response, CD4 and MHCII. This suggests that lack of lymphoid cells in NSG mice leads to a perpetual recruitment of macrophage cells and a worsening damage to the kidney in CKD. Interestingly, unlike C57BL/6N-CKD mice, removing adenine diet after 4 days in NSG-CKD mice completely recovered kidney function (BUN, NGAL, KIM-1) at 14 days. More work is underway to phenotype lymphoid subpopulations which may aggravate injury but boost repair during recovery in adenine-induced CKD.
Conclusion
This data highlights the need to unravel the dichotomy of inflammatory actions of lymphoid subpopulations, as T-regulatory and cytotoxic T-cells in CKD.