Deciphering the links between chronic kidney disease, senescence and obesity.

Chronic kidney disease (CKD) is a serious and increasing public health issue affecting more than 10% of the global population. In recent years, obesity and aging have become increasingly important risk factors for the development of CKD. Growing evidence points out that cellular senescence is a crucial driver in the pathogenesis of CKD. At the cellular level, senescence leads to metabolic alterations. However, little is known about the underlying molecular mechanisms in renal senescent cells. Therefore, this study aimed to develop a reliable in vitro model of renal senescence to examine the associated metabolic dysfunctions and the putative bidirectional link between senescence and lipotoxicity. Here, we developed a renal senescence model by exposing human kidney cells (HK-2) to 500 µM of hydrogen peroxide (H2O2) for two hours. In parallel, lipotoxicity was induced by exposure to palmitate (PA) or BSA (vehicle) for 24 hours. Five days after exposure to H2O2, HK-2 cells exhibited well-known senescence features such as enlarged cellular and nuclear sizes, senescence-associated β-galactosidase (SA-β-gal) staining, γH2AX foci, upregulation of IL6 and IL8 genes, cell cycle arrest and loss of lamin B1. Interestingly, disturbances in lipid metabolism were also measured, as evidenced by lipid droplet accumulation and upregulation of the fatty acid synthase (FAS) gene. Here, cellular senescence induced lipotoxicity in HK-2 cells, but little is known about the impact of lipotoxicity on senescence onset. Therefore, to determine whether there is a bidirectional link between senescence and lipotoxicity, HK-2 cells were exposed to PA. Preliminary data indicate that these cells did not present any morphological change or SA-β-gal staining. In conclusion, these results show that this robust renal senescent cell model can be used to study tubular senescence and the underlying metabolic alterations.