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Cell Cycle and Senescence Regulation by Podocyte Histone Deacetylase 1 and 2.

Background: Intact expression of podocyte histone deacetylases (HDAC) during development is essential for maintaining a normal glomerular filtration barrier due to its role in modulating DNA damage and preventing premature senescence. Methods: Germline podocyte-specific Hdac1 and 2 (Hdac1/2) double knockout mice were generated to examine the importance of these enzymes during development. Results: Podocyte-specific loss of Hdac1/2 in mice resulted in severe proteinuria, kidney failure, and collapsing glomerulopathy. Hdac1/2-deprived podocytes exhibited classic characteristics of senescence, such as senescence-associated β-galactosidase activity and lipofuscin aggregates. In addition, DNA damage, likely caused by epigenetic alterations such as open chromatin conformation, not only resulted in podocyte cell-cycle entry as shown in vivo by Ki67 expression and by FUCCI-2aR mice, but also in p21-mediated cell-cycle arrest. Through the senescence secretory associated phenotype, the damaged podocytes secreted proinflammatory cytokines, growth factors, and matrix metalloproteinases, resulting in subsequent podocyte detachment and loss, evidenced by senescent podocytes in urine. Conclusions: Hdac1/2 play an essential role during development. Loss of these genes in double knockout mice leads to sustained DNA damage and podocyte senescence and loss.