Abstract: TH-OR15
Induced Senescent Cells Recruit Leukocytes and Permit Their Own Clearance from Healthy Young Kidneys
Session Information
- CKD Mechanisms: Prediction, Propagation, and Prevention
November 02, 2023 | Location: Room 119, Pennsylvania Convention Center
Abstract Time: 05:06 PM - 05:15 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Docherty, Marie, The University of Edinburgh Centre for Inflammation Research, Edinburgh, Edinburgh, United Kingdom
- Reck, Maximilian, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, Edinburgh, United Kingdom
- Campbell, Ross Alexander, The University of Edinburgh Centre for Inflammation Research, Edinburgh, Edinburgh, United Kingdom
- Baird, David Paul, The University of Edinburgh Centre for Inflammation Research, Edinburgh, Edinburgh, United Kingdom
- Denby, Laura, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, Edinburgh, United Kingdom
- Mylonas, Katie J., The University of Edinburgh Centre for Inflammation Research, Edinburgh, Edinburgh, United Kingdom
- Ferenbach, David A., The University of Edinburgh Centre for Inflammation Research, Edinburgh, Edinburgh, United Kingdom
Background
Increasing evidence links senescent epithelia to fibrosis and functional loss in experimental and human kidney disease. Whether senescent cells themselves are sufficient to initiate and sustain kidney fibrosis is unknown. We hypothesised that induction of epithelial senescence alone, in absence of other renal injuries, is sufficient to initiate and sustain fibrosis.
Methods
We generated a Pax8creERT2;mdm2 fl/fl mouse (‘TG’) via a cross of two established stains and treated these and wild type (WT) mice with tamoxifen by oral gavage to induce epithelial restricted senescence via mdm2 deletion. Markers of fibrosis (Collagen I) and growth arrest (p21cip1) were quantified by immunofluorescence (IF), and total collagen by picrosirius red. Full transcriptomic analysis was undertaken using scRNA-seq (10X).
Results
Tamoxifen resulted in p21cip1 induction in renal epithelia in TG but not in wild WT mice by IF (10.45 ± 2.9 vs 3.15 ± 0.7, p<0.05). On scRNA-seq, TG (but not WT) kidneys contained transcriptionally distinct, cdkn1a+ epithelia, recruited leukocytes and increased activated myofibroblasts. IF confirmed increased renal fibrosis at D7 in TG vs WT (Collagen1 1.1 ± 0.3 vs 3.1 ± 0.5, p<0.005). By D42, scRNAseq analysis demonstrated clearance of cdkn1a+ senescent epithelia, normalisation of leukocyte counts and resolution of myofibroblast activation in TG kidneys, with confirmation by IF; showing no difference in p21cip1 levels between WT and TG mice (2.4 ± 1.4 vs 4.1 ± 1.1, p=0.7) and no progressive fibrosis.
Conclusion
Our results demonstrate that epithelial senescence is profibrotic in absence of injury to other cell lineages. Of importance, mechanisms in the healthy adult kidney allow detection and physiologic clearance of senescence and prevent ongoing fibrosis. Understanding how these pathways are lost with age and chronic injury may lead to new routes to promote clearance of profibrotic senescent epithelia.