Abstract
Apoptosis is a major cause of reduced podocyte numbers, which leads to proteinuria and/or glomerulosclerosis. Emerging evidence has indicated that deSUMOylation, a dynamic post-translational modification that reverses SUMOylation, is involved in the apoptosis of Burkitt’s lymphoma cells and cardiomyocytes; however, the impact of deSUMOylation on podocyte apoptosis remains unexplored. The p53 protein plays a major role in the pathogenesis of podocyte apoptosis, and p53 can be SUMOylated. Therefore, in the present study, we evaluated the effect of p53 deSUMOylation, which is regulated by sentrin/SUMO-specific protease 1 (SENP1), on podocyte apoptosis. Our results showed that SENP1 deficiency significantly increases puromycin aminonucleoside (PAN)-induced podocyte apoptosis. Moreover, SENP1 knockdown results in the accumulation of SUMOylated p53 protein and the increased expression of the p53 target pro-apoptotic genes, BAX, Noxa and PUMA, in podocytes during PAN stimulation. Thus, SENP1 may be essential for preventing podocyte apoptosis, at least partly through regulating the functions of p53 protein via deSUMOylation. The regulation of deSUMOylation may provide a novel strategy for the treatment of glomerular disorders that involve podocyte apoptosis.
Highlights
Clinical and experimental studies have revealed that a decrease in podocyte number is closely associated with the initiation of glomerulosclerosis and contributes to the progression of chronic kidney disease (CKD) [1,2,3,4]
To test the presence of puromycin aminonucleoside (PAN)-induced apoptosis in podocytes, we initially detected the amount of apoptosis in MPC5 cells using FACS analysis and found that apoptotic MPC5 cells progressively increased after PAN treatment (Figure 1A,B)
As it is unclear whether PAN stimulation leads to changes in SENP1 expression in podocytes, we simultaneously examined the expression of SENP1 in PAN-treated MPC5 cells
Summary
Clinical and experimental studies have revealed that a decrease in podocyte number is closely associated with the initiation of glomerulosclerosis and contributes to the progression of chronic kidney disease (CKD) [1,2,3,4]. SUMOylation is a crucial post-translational modification of targeted proteins, which is characterized by the covalent conjugation of a small peptide (SUMO) [8,9]. We observed that SENP1 deficiency resulted in a significant increase in the rate of podocyte apoptosis induced by PAN. The inhibition of SENP1 promoted the accumulation of SUMOylated p53 protein and the transcription of p53-dependent pro-apoptotic genes, including BAX, Noxa and PUMA, that are otherwise induced by PAN stress. Our results indicate that SENP1 may contribute to preventing podocytes from undergoing PAN-induced apoptosis. This provides new insights into the mechanism of glomerular dysfunction, and suggests that the deSUMOylation of the p53 protein might represent a novel therapeutic strategy for the treatment of glomerular disorders
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