Abstract: FR-PO1090
Regenerative Capacity Decline and Progressive Tubular Cell Polyploidization as Adaptive Kidney Tubule Response to Aging
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Lazzeri, Elena, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Antonelli, Giulia, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- De Chiara, Letizia, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Romagnani, Paola, Universita degli Studi di Firenze, Firenze, Italy
Background
Kidney function declines progressively with age, leading to chronic kidney disease (CKD) in the elderly. CKD is a major global health problem, explaining why there is the need to understand the age-related mechanisms in CKD development. Most adult organs contain a pool of stem cells, whose function decline leads to tissue ageing. To what extent do resident stem cells or differentiated cells contribute to organ ageing remain to be clarified. Recently, we revealed two response programs in the kidney tubule to recover kidney function and a structural integrity upon AKI. On the one hand, a population of resident renal progenitors (RPC) self-renew and differentiate to replace lost tubular cells. On the other, tubular cells (TC) undergo endoreplication to become polyploid. We aimed to study how these two mechanisms affected the kidney ageing.
Methods
To study RPC, we used the inducible Pax2/Confetti mice, in which RPC (Pax2+cells) are randomly labelled by one of the four fluorescent reporter genes. To identify polyploid TC, we used two inducible mouse models: the heterozygous Pax8/Confetti mice and Pax8/FUCCI2aR mice. In the former model, all TC are labelled randomly by one of the four fluorescent reporter genes. Polyploid TC appear as bi-coloured due to recombination of two fluorochromes in the same cell. In the second model, polyploid TC are identified by expression of cell cycle fluorescent proteins (FUCCI2aR technology) in combination with DNA content analysis. Mice were analyzed at 2, 6, 12 and 18 months of age.
Results
Pax2/Confetti mice revealed that Pax2+RPC of proximal tubule declined during ageing and their clonogenic capacity is impaired. By contrast, Pax8/Confetti mice showed an increase of polyploid TC during ageing. Analysis of aged Pax8/FUCCI2aR mice revealed that polyploid TC increased furtherly their DNA content by going through additional cell cycles and that this was associated with fibrosis, senescence and kidney function decline. Thus, while the pool of RPC is progressively lost during ageing, impairing the kidney tubule regenerative capacity, TC enter the cell cycle to become polyploid. These accumulate in aged kidneys and trigger fibrosis and senescence, leading to CKD.
Conclusion
These results suggest a previously unknown role for RPC and polyploid TC in kidney tubule response to ageing.