Delivery of Senolytics Can Help Following Acute Kidney Injury, but Tissue Damage and Loss of Function Remains

Researchers here investigate the mechanisms by which senescent cells are created during acute kidney injury (AKI). Senescent cells are usually created as a part of the injury and regeneration process, and then destroyed quickly afterwards, but there is more to it in this case. The senescent cells linger and their signaling causes fibrosis, a form of scarring that further harms the injured kidney. The researchers find that some (but not all) senolytic drugs can clear out these senescent cells, reducing fibrosis. However, introducing this treatment after AKI failed to lead to regeneration of damage to the tubule structures of the kidney. That only some senolytics work for this particular type of senescent cell and tissue is perhaps the most interesting finding here: it reinforces the developing thesis that there are significant differences between senescent cells in different tissues and circumstances, and thus variety is desirable in the development programs for small molecule senolytic drugs.

Tubule repair is a common event after kidney injury, but is frequently associated with interstitial inflammation and maladaptive processes that lead to fibrosis, the hallmark of all forms of kidney disease and a reliable predictor of progression to chronic kidney disease(CKD). Recently, multiple studies identified multipotent mesenchymal stromal progenitor cells (pericytes) as the cell population that is responsible for collagen deposition after injury. Kidney fibrosis has also been correlated with arrest of tubular epithelial cells (TECs), which suggests that the epithelium plays a primary role in the progression of kidney disease. However, the factors that contribute to the cell cycle arrest are not known. Cell cycle arrest is a universal marker of cellular senescence and is evoked by a variety of stressors.

Several studies have reported a correlation between the presence of senescent cells and kidney fibrosis both during the aging process and in the context of disease, but a systematic study of cellular senescence after AKI and its potential contribution to the progression of tubular damage and fibrosis is lacking. Here, we show that in mice TECs commonly become senescent after various types of kidney injury, and that this occurs surprisingly early after injury. We show that senescent TECs express higher levels of proinflammatory factors of the SASP as a result of cell-autonomous control by the TLR/IL-1R-mediated innate immune signaling pathway, and that senescent TECs are a source of the mesenchymal progenitor-activating ligands.

Tubule-specific inhibition of TLR/IL-1R signaling by conditional inactivation of the Myd88 gene prior to senescence not only reduced the levels of epithelial cell-derived proinflammatory cytokines, interstitial infiltration, and fibrosis, but also decreased the accumulation of senescent cells and ameliorated tubular damage. Whereas inactivation soon after injury was equally effective in decreasing the number of senescent TECs, inflammation, and fibrosis, it did not protect from tubular damage. Similarly, eliminating p16+ senescent cells, but not senescent cells by FOXO4-DRI inhibitory peptide, which induces apoptosis of senescent cells by disrupting the interaction between FOXO4 and p53, reduced kidney fibrosis without reducing tubular damage.

Our results indicate that TEC senescence is a common and early event after kidney injury, and that signaling by the TLR/IL-1R pathway within the epithelium controls this phenomenon. Our findings also suggest that early intervention after injury is likely required to reduce organ damage after AKI. Furthermore, this study reveals what we believe is a novel function of the epithelial TLR/IL-R1 signaling in controlling the onset of TEC senescence in a cell-autonomous manner, consistent with the concept that the tubular epithelium triggers kidney disease following injury and also drives its progression.



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