Cellular Senescence Limits Regenerative Capacity and Allograft Survival

Abstract

Long-term graft survival after kidney transplantation remains unsatisfactory and unpredictable. Interstitial fibrosis and tubular atrophy are major contributors to late graft loss; features of tubular cell senescence, such as increased p16INK4a expression, associate with these tubulointerstitial changes, but it is unknown whether the relationship is causal. Here, loss of the INK4a locus in mice, which allows escape from p16 INK4a -dependent senescence, significantly reduced interstitial fibrosis and tubular atrophy and associated with improved renal function, conservation of nephron mass, and transplant survival. Compared with wild-type controls, kidneys from INK4a 2/2 mice developed significantly less interstitial fibrosis and tubular atrophy after ischemia-reperfusion injury. Consistently, mice that received kidney transplants from INK4a/ARF 2/2 donors had significantly better survival 21 days after life-supporting kidney transplantation and developed less tubulointerstitial changes. This correlated with higher proliferative rates of tubular cells and significantly fewer senescent cells. Taken together, these data suggest a pathogenic role of renal cellular senescence in the development of interstitial fibrosis and tubular atrophy and kidney graft deterioration by preventing the recovery from injury. Inhibiting premature senescence could have therapeutic benefit in kidney transplantation but has to be balanced against the risks of suspending antitumor defenses.

Complement Modulation of Anti-Aging Factor Klotho in Ischemia/Reperfusion Injury and Delayed Graft Function

“…In addition, decreased serum levels of renal-derived Klotho (20) might also have systemic and renal adverse consequences considering its pleiotropic functions including cytoprotection (27), preservation of endothelial function (28), inhibition of fibrosis (21,29). Klotho has also antioxidant, anti-inflammatory, and anti-senescence functions (12), that might support the regeneration of TEC maintaining nephron integrity (10,30). In conclusion, our data demonstrate for the first time a direct involvement of complement in Klotho down-regulation in IRI.…”

Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments

“…3 All of the aforementioned analyses were performed by blinded observation of 12 random nonoverlapping visual fields (2003 magnification). Glomeruli and vessels larger than the size of adjacent tubules were not included in the analysis.…”

“…1 Among the involved mechanisms, cellular senescence has emerged as an important factor disturbing renal regeneration and promoting kidney aging. [2][3][4][5] Cellular senescence is a state of irreversible growth arrest resulting from telomere dysfunction or various cellular stresses that activate cyclin-dependent kinase inhibitors, particularly p16 INK4a . We have previously shown that ischemia/ reperfusion (I/R) -related cell stress enhances the expression of p16…”

“…3 Another cellular mechanism that seems to be important in the outcome of AKI is autophagy. Autophagy is an evolutionarily conserved pathway that plays a central role in turnover of proteins and degradation of damaged organelles.…”

The impact of autophagy on the development of senescence in primary tubular epithelial cells

“…12 In support of this view, we have observed that experimental ablation of p16 INK4a -driven senescence leads to a favorable outcome after AKI and to improved graft survival. 13 Most recently, Baker and colleagues have shown that clearance of p16…”