Abstract: FR-PO1195
Loss of Polyploidy and Regenerative Capacity in Kidney Tubules Contributes to CKD During Aging
Session Information
- CKD: Mechanisms, AKI, and Beyond - 2
November 07, 2025 | Location: Exhibit Hall, 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, Florence, Tuscany, Italy
- Antonelli, Giulia, Universita degli Studi di Firenze, Florence, Tuscany, Italy
- Romagnani, Paola, Universita degli Studi di Firenze, Florence, Italy
Background
Aging is associated with a decline in nephron number, contributing to decreased kidney function and chronic kidney disease (CKD). Understanding the mechanisms, that drive CKD in aging, is clinically relevant. Two such mechanisms include renal progenitor cells (RPCs), which aid in tissue regeneration after injury, and polyploid tubular cells (TCs), which undergo genome duplication and hypertrophy to sustain kidney function after injury. This study aims to investigate these responses during aging.
Methods
To trace RPCs (Pax2+cells) we used inducible Pax2/Confetti mice. To study polyploid TCs we used inducible Pax8/Confetti and Pax8/FUCCI2aR mice. Analysis at 2, 5, 12 and 20months (m) of age. scRNA seq analysis at 2 and 20m of age.
Results
During aging we observed a progressive decline in kidney function, accompanied by nephron and TC loss, followed by increased TC hypertrophy, suggesting a diminished regenerative capacity and polyploidy-driven hypertrophy as mechanisms involved. In h-Pax8/Confetti and Pax8/FUCCI2aR mice, as kidney function reduced, we observed an increase in cycling polyploid TCs, culminating in the emergence of octaploid TCs. Notably, this early response, declined after 12m, leading to further functional deterioration. Similarly, in Pax2/Confetti mice, we observed a clonal expansion of Pax2+RPC, which peaked later at 12m and diminished by 20m. Overall, TC polyploidization precedes RPC expansion, with both responses deteriorating at 20m. scRNA seq uncovered an age related shift toward a stressed, pro-senescent, and pro-fibrotic phenotype for RPCs and polyploid TCs and identified SPP1 (encoding osteopontin, OPN) signaling as the most relevant pathway in old mice. In vitro, OPN treatment led to RPC growth arrest and reduced polyploid TCs, favouring the acquisition of a fibrotic and senescent state and explaining the reduced regenerative and polyploid response in aging.
Conclusion
The polyploid response is the first line of action to withstand to the decline of kidney function during aging, followed by the regenerative response. However, both these responses reduced in old mice, contributing to CKD. SPP1 signaling emerges as crucial in contributing RPC exhaustion and polyploid TC depauperation, explaining the decline of kidney function and highlighting a potential therapeutic target to preserve kidney function during aging.