Kidney fibrosis, a common endpoint of chronic kidney disease (CKD), is strongly linked to aging, with cellular senescence emerging as a key driver in its pathogenesis. This overview synthesizes current knowledge on how senescent cells contribute to renal fibrosis, focusing on their mechanisms, identification, and potential therapeutic interventions.
Cellular senescence is a state of permanent cell cycle arrest characterized by features like 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, including tubular epithelial cells, podocytes, endothelial cells, and fibroblasts, drive fibrosis through paracrine signaling and immune activation. For example, senescent tubular cells secrete pro-inflammatory cytokines (IL-6, TNF-α) and profibrotic factors (TGF-β, CTGF), promoting epithelial-mesenchymal transition (EMT) and extracellular matrix deposition. In diabetic kidney disease, senescent glomerular and tubular cells correlate with disease severity, while in acute kidney injury (AKI) models, persistent senescence in proximal tubular cells accelerates progression to CKD.
Identifying senescent cells requires a multi-step approach, combining SA-β-gal staining, absence of proliferation markers (e.g., Ki-67), and assessment of SASP components. However, challenges persist due to marker heterogeneity; for instance, SA-β-gal activity can occur in non-senescent cells, and SASP composition varies by cell type and stressor. Different types of senescence, such as replicative, stress-induced, and oncogene-induced, exhibit distinct triggers and roles. Acute senescence may aid tissue repair, while chronic senescence, marked by prolonged SASP secretion and apoptosis resistance, exacerbates fibrosis. In AKI models, acute senescence in tubular cells is initially adaptive but can transition to chronic senescence with persistent injury, leading to maladaptive repair and fibrosis.
Key signaling pathways driving renal cellular senescence include TGF-β/Smads, which induce p16/p21-mediated cell cycle arrest and SASP secretion. In unilateral ureteral obstruction (UUO) models, TGF-β1 upregulation promotes tubular senescence and fibrosis, while klotho, an anti-aging protein, inhibits this pathway. The Wnt/β-catenin pathway, activated in CKD, promotes senescence by upregulating pro-fibrotic genes and interacting with RAS signaling. NF-κB, central to SASP regulation, is activated by DNA damage and oxidative stress, enhancing inflammatory cytokine production in senescent renal cells. Other pathways like Nrf2/ARE (antioxidant response) and mTOR (regulating autophagy and longevity) also influence senescence; mTOR inhibition with rapamycin reduces senescent cell accumulation in aging kidneys.
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, improving renal function and reducing fibrosis. FOXO4-DRI, a peptide that induces apoptosis in senescent cells, and glutaminase inhibitors, which deplete senescent cell energy sources, show promise in preclinical studies. Senomorphics like metformin (AMPK activator) and klotho supplementation mitigate senescence by inhibiting TGF-β signaling and improving mitochondrial function. Rapamycin, an mTOR inhibitor, delays renal aging by suppressing SASP and promoting autophagy.
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 CKD patients where comorbidities complicate treatment.
In summary, cellular senescence is a central driver of kidney fibrosis, with senescent cells from multiple renal lineages contributing to inflammatory and fibrogenic pathways. Targeting senescence through senolytics or senomorphics offers novel therapeutic opportunities, but further research is needed to address heterogeneity and translate preclinical findings to clinical practice. Advances in multi-omics and model systems will enhance understanding of senescence’s role in CKD, paving the way for personalized antifibrotic therapies.
DOI: 10.1007/s11684-024-1117-z