Targeting Senescent Cells as Therapy for CKD.

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.

Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis.

Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1 cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1 cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells.

Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis.

Progressive fibrosis and maladaptive organ repair result in significant morbidity and millions of premature deaths annually. Senescent cells accumulate with aging and after injury and are implicated in organ fibrosis, but the mechanisms by which senescence influences repair are poorly understood. Using 2 murine models of injury and repair, we show that obstructive injury generated senescent epithelia, which persisted after resolution of the original injury, promoted ongoing fibrosis, and impeded adaptive repair.

The Role of Ageing and Parenchymal Senescence on Macrophage Function and Fibrosis.

In this review, we examine senescent cells and the overlap between the direct biological impact of senescence and the indirect impact senescence has its effects on other cell types, particularly the macrophage. The canonical roles of macrophages in cell clearance and in other physiological functions are discussed with reference to their functions in diseases of the kidney and other organs. We also explore the translational potential of different approaches based around the macrophage in future interventions to target senescent cells, with the goal of preventing or reversing pathologies driven or contributed to in part by senescent cell load