Sexual Dimorphism in the Regenerative and Polyploid Response of Kidney Tubule during Aging

Background: Kidney function declines with age, leading to chronic kidney disease (CKD). Although a higher prevalence of CKD in females, men experience a faster CKD progression. The cellular mechanisms underlying this difference in CKD development during ageing remain to be clarified. A link has been hypothesized between a regenerative and polyploid response and ageing. Whereas the decline in the regenerative potential of stem cells is associated with tissue ageing, the increase of polyploidy preserves tissue function during ageing. In the kidney, a regenerative and polyploid response takes place after AKI. Whereas renal progenitors (RPC) generate new tubular cells (TC) to recover structural integrity, TC enter alternative type of cell-cycle to become polyploid and to recover kidney function. Here, we aimed to investigate how these two adaptive responses act differently in females and males during ageing. Methods: Female and male mice were analyzed at 2, 6, 12, 20 months of age. Pax2/Confetti mice were used to study the regenerative response driven by RPC (Pax2+cells). Pax8/FUCCI2aR and h-Pax8/Confetti mice were used to study the polyploid response. In the first one polyploid TC are identified by combining DNA content with FUCCI2aR technology. In the second one polyploid TC are identified as multicolored TC following recombination of Confetti reporter genes. scRNAsequencing was performed in female and male mice at 2 and 20 months of age. Results: During ageing, male mice experienced an earlier and faster kidney function decline than females. Pax2/Confetti mice revealed that females were endowed with a higher number of RPC, which have a greater capacity to expand clonally, showing a better regenerative capacity than males during ageing. Analysis of the polyploid response in Pax8/FUCCI2aR and in h-Pax8/Confetti mice revealed that whereas the polyploid fraction increased in aged females, it was reduced in aged males. Indeed, polyploid TC in aged males accumulated DNA damage, which resulted in additional rounds of polyploidization, genetic instability and death. scRNAsequencing analysis profiled the ageing-related stress responses of polyploid TC in aged males. Conclusion: These insights might explain why females are more capable to compensate kidney function decline, whereas males are more susceptible to an earlier and faster progression to CKD during ageing.