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

Abstract

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-specificHdac1and2(Hdac1/2) double knockout mice were generated to examine the importance of these enzymes during development.Results:Podocyte-specific loss ofHdac1/2in 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 shownin vivoby 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:Hdac1/2play an essential role during development. Loss of these genes in double knockout mice leads to sustained DNA damage and podocyte senescence and loss.

Podocyte Senescence and Aging

“…17 This includes podocytes that undergo cell cycle arrest on differentiation. [18][19][20][21][22] Thus, at least in postmitotic cells, the pathways required for cell cycle arrest and those for senescence are independent. 17 Finally, it is important to emphasize that senescence is a double-edged sword.…”

“…92 Yet, it may have the opposite effect in the glomerulus because inhibiting/deleting HDAC1/2 in podocytes enhances rather than improves senescence. 22 Finally, it is important to note that removing senescent podocytes from glomeruli may not be the most advisable therapeutic strategy because removal of senescent podocytes causes podocyte depletion, which equates to glomerular injury.Senomorphics: This class of small molecules aims to suppress all or at least several characteristics of the senescence phenotype without killing the cells. 93 Among those, metformin and rapamycin inhibit senescence and SASP by inducing autophagy, thereby reducing the accumulation of damaged organelles.…”

Kdm6a-CNN1 axis orchestrates epigenetic control of trauma-induced spinal cord microvascular endothelial cell senescence to balance neuroinflammation for improved neurological repair

“…Specific Hdac1/2 deletion could induce podocyte senescence, which generated a high amount of SASP including pro-inflammatory cytokines to damage podocyte, ultimately resulting in increased proteinuria and progressive renal failure. 17 Ezh2, a histone methylase, has been found to stimulate Foxo1 expression by targeting H3K27me3. This process results in a decrease in the antioxidant potential of bone marrow stromal cells (BMSCs) and contributes to the senescence of BMSCs.…”

C/EBPβ isoform‐specific regulation of podocyte pyroptosis in lupus nephritis‐induced renal injury

“…These glomerular mechanisms may be responsible for the diverse clinical, biochemical, and histological manifestations of renal disease [3]. Podocytes, which are differentiated cells with a high degree of specialization, make up the glomerular filtration barrier's top layer [4]. Due to podocytes' limited capacity for regeneration, damage or loss of podocytes could result in the destruction of the glomerular filtration membrane.…”