Targeted elimination of senescent cells to protect kidneys against ischemia reperfusion injury

H. van Willigenburg, R.W.F. de Bruin, P.L.J. de Keizer

Friday 16 march 2018

10:10 - 10:15h at Willem Burger Foyer

Categories: Basic, Session (poster)

Parallel session: Poster session 8: Basic translational research

Transplantation induced damage, which is mainly caused by ischemia reperfusion injury (IRI), reduces graft function and survival and is therefore an important subject of research.

Accumulation of damage in an organ, and the inability to effectively cope with this can result in subsets of cells entering a state called senescence. Senescence is characterized by a permanent cell cycle arrest and development of a chronic pro-inflammatory state; the so called senescence associated secretory phenotype (SASP), which negatively affects the surrounding tissue. Due to their permanent cell cycle arrest senescent cells reduce the regenerative capacity of the tissue. These cell types are of high interest in anti-aging research, as these cells accumulate with age, but we argue these cells are of interest in transplantation associated damage as well.

We have shown that two months after renal IRI, induced by bilateral kidney clamping, there is an increased expression of several validated senescence markers, such as p16^Ink4a, Interleukin-6 and chemokine (C-C motif) ligand 2 (CCL2), whilst downregulated expression of LaminB1 which is lost in senescent cells. The increase in senescent cell levels 2 months after IRI is accompanied by poor kidney function, compared to SHAM operated mice.

As senescent cells are known to negatively influence surround tissue through SASP, we aim to remove these senescent cells and improve kidney transplant outcome by the targeted eradication of senescent cells. For the first time, we have a therapeutic compound (Proxofim) to target senescence in vivo and improve kidney function in mouse models for kidney aging (Baar et al, 2017). Proxofim was shown to reduce improve kidney function of aged mice and reduce inflammation levels as a result of the targeted elimination of senescent cells. Therefore we are using Proxofim to overcome transplantation associated injury and improve kidney function.