Cellular Senescence Is a Central Driver of Chronic Kidney Disease–Related Kidney Fibrosis

In a review published in Frontiers of Medicine, study investigators summarize the features of the cellular senescence of the kidney and showcase the possible functions of senescent cells in the pathogenesis of kidney fibrosis as a result of chronic kidney disease (CKD). Additionally, they note pharmacological approaches that specifically target senescent cells can be utilized to mitigate the progression of kidney fibrosis in patients with CKD.¹

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Kidney fibrosis is a common end point of CKD, with cellular senescence emerging as a key driver in its pathogenesis. Despite great progress in research in recent years, there are currently no targeted antifibrotic therapies that have been approved to mitigate progression. Epidemiologic, clinical, and molecular evidence suggests that aging is a major contributor to the increasing incidence of CKD. Of note, senescent renal tubular cells, fibroblasts, endothelial cells, and podocytes have been detected within the kidneys of patients and animal models with CKD.^1,2

Although accumulated evidence supports the essential role of cellular senescence within CKD, the mechanisms that promote cell senescence and how senescent cells contribute to CKD remain largely unknown. The authors’ overview combines current knowledge on how senescent cells contribute to renal fibrosis, particularly focusing on their mechanisms, identification, and potential therapeutic interventions that can be leveraged.¹

Cellular senescence is a state of permanent cell cycle arrest that is characterized by certain features, such as senescence-associated β-galactosidase (SA-β-gal) activity, upregulated cyclin-dependent kinase inhibitors (p16, p21), and the senescence-associated secretory phenotype (SASP). Accumulated senescent cells in the kidney (eg, tubular epithelial cells, podocytes, endothelial cells, fibroblasts) are the key drivers of fibrosis through paracrine signaling and immune activation. As an example, the authors note that senescent tubular cells secrete proinflammatory cytokines (IL-6, TNF-α) and profibrotic factors (TGF-β, CTGF), which promote epithelial-mesenchymal transition (EMT) and extracellular matrix deposition. Specifically in diabetic kidney disease, senescent glomerular and tubular cells are associated with severity of disease, whereas in acute kidney injury (AKI) models, persistent senescence in proximal tubular cells accelerates progression to CKD.^1,2

According to the authors, identifying these senescent cells requires a multistep approach, one that involves the combination of SA-β-gal staining, absence of proliferation markers (eg, Ki-67), and assessment of SASP components; however, challenges often persist because of marker heterogeneity. For example, SA-β-gal activity can occur in nonsenescent cells, and SASP composition varies by cell type and stressor. Different types of senescence (eg, replicative, stress-induced, oncogene-induced) can show distinct triggers and roles. Acute senescence may aid in the repair of tissue, whereas chronic senescence—which is marked by prolonged SASP secretion and apoptosis resistance—worsens fibrosis. In AKI models, acute senescence in tubular cells is initially adaptive; however, it can transition to chronic senescence with persistent injury, leading to maladaptive repair and fibrosis.^1,2

Key signaling pathways that promote renal cellular senescence include TGF-β/Smads, which induce p16/p21-mediated cell cycle arrest and SASP secretion. In unilateral ureteral obstruction models, TGF-β1 upregulation promotes tubular senescence and fibrosis, whereas the anti-aging protein klotho inhibits this pathway. The Wnt/β-catenin pathway, which is activated in CKD, promotes senescence by upregulating profibrotic genes and interacting with RAS signaling.²

Therapeutic strategies targeting senescence include senolytics (drugs that eliminate senescent cells) and senomorphics (agents that mitigate SASP). Senolytics such as ABT-263 (Bcl-2/Bcl-xL inhibitor) and dasatinib plus quercetin reduce senescent cells in AKI and lupus nephritis models, improve renal function, and reduce fibrosis. Additionally, senomorphics such as metformin (AMPK activator) and klotho supplementation alleviate senescence by hindering TGF-β signaling and improving mitochondrial function.²

Despite progress, challenges remain, including senescent cell heterogeneity and SASP variability. Single-cell transcriptomics and spatial technologies may help characterize distinct senescent subtypes in renal fibrosis. Additionally, most preclinical studies use immortalized cell lines, which may not fully recapitulate primary cell behavior. Clinical translation requires rigorous evaluation of senotherapeutics’ safety and efficacy in large trials, particularly in patients with CKD where comorbidities complicate treatment.

The authors note that advances in multiomics and model systems may enhance the understanding of senescence’s role within CKD, paving the way for more personalized antifibrotic therapies.¹

REFERENCES

1. Yang L, Ma L, Fu P, Nie J. Update of cellular senescence in kidney fibrosis: from mechanism to potential interventions. Front. Med. 19, 250–264 (2025). doi:10.1007/s11684-024-1117-z

2. Higher Education Press. Update of cellular senescence in kidney fibrosis: from mechanism to potential interventions. News release. May 22, 2025. Accessed May 29, 2025. https://www.eurekalert.org/news-releases/1084891