Targeting Senescent Cells as Therapy for CKD

Abstract

Senescent cells accumulate in the kidney with aging, after acute and chronic injuries, and are present in increased numbers in deteriorating kidney transplants. Senescent cells have undergone permanent cell cycle arrest and release many proinflammatory cytokines/chemokines and profibrotic factors: the senescence-associated secretory phenotype. Recent work from several groups including our own has shown that senescent cells play a causative role in progression of kidney disease. Experimental evidence also indicates that targeting senescent cells has potential to alter the renal regenerative response, reducing progressive fibrosis and improving functional recovery after injury. Research and clinical interest is focused on understanding how accumulating chronic senescent cells link acute injury to progressive fibrosis, dysfunction, and mortality in human CKD. In this review, we outline current protocols for the identification of how senescent cells are identified in vitro and in vivo. We discuss the proposed mechanisms of actions of first-generation senolytic and senomorphic agents, such as ABT-263 (navitoclax) which targets the BCL2 family of survival factors, and senomorphic agents such as metformin which targets aspects of the senescence-associated secretory phenotype. We also review that emerging technologies, such as nanocarriers, are now being developed to have safer delivery systems for senolytics, greater specificity, fewer off-target effects, and less toxicity. Other methods of senescent cell elimination being developed target various immune evasion tactics displayed by these cells. By understanding the role of senescence in kidney homeostasis and disease, developing new, targeted compounds and the tools to allow their efficacy to be charted noninvasively, it should become possible for senolytic treatments to move from the bench to bedside.