Targeting cellular senescence in kidney diseases and aging: A focus on mesenchymal stem cells and their paracrine factors

Abstract

Cellular senescence is a phenomenon distinguished by the halting of cellular division, typically triggered by DNA injury or numerous stress-inducing factors. Cellular senescence is implicated in various pathological and physiological processes and is a hallmark of aging. The presence of accumulated senescent cells, whether transiently (acute senescence) or persistently (chronic senescence) plays a dual role in various conditions such as natural kidney aging and different kidney disorders. Elevations in senescent cells and senescence-associated secretory phenotype (SASP) levels correlate with decreased kidney function, kidney ailments, and age-related conditions. Strategies involving senotherapeutic agents like senolytics, senomorphics, and senoinflammation have been devised to specifically target senescent cells. Mesenchymal stem cells (MSCs) and their secreted factors may also offer alternative approaches for anti-senescence interventions. The MSC-derived secretome compromises significant therapeutic benefits in kidney diseases by facilitating tissue repair via anti-inflammatory, anti-fibrosis, anti-apoptotic, and pro-angiogenesis effects, thereby improving kidney function and mitigating disease progression. Moreover, by promoting the clearance of senescent cells or modulating their secretory profiles, MSCs could potentially reverse some age-related declines in kidney function.This review article intends to shed light on the present discoveries concerning the role of cellular senescence in kidney aging and diseases. Furthermore, it outlines the role of senotherapeutics utilized to alleviate kidney damage and aging. It also highlights the possible impact of MSCs secretome on mitigating kidney injury and prolonging lifespan across various models of kidney diseases as a novel senotherapy.

Keywords: Acute kidney injury; Cellular senescence; Chronic kidney disease; Kidney aging; Mesenchymal stem cells; Secretome of MSCs.

Fig. 1

The physiological differences in the aged kidney. The differences between (A) younger and (B) aged kidney. Renal aging is influenced by various factors including gender, genetic background, race, and pivotal mediators like oxidative and nitrosative stresses, chronic inflammation, RAAS, hormones (sex hormones, Klotho, FGF-23), diminished kidney function and repair capabilities, and underlying cardiovascular conditions. The irreversible and permanent growth arrest of senescent cells, imbalance of proliferation/apoptosis, and reduced repair after organ damage are the central paradigm of kidney aging, decreasing repair after injury, and increasing sensitivity to injury. Vascular changes, glomerular hypertrophy, EC injury, mesangial cell expansion, PEC loss, and tubular changes are presented in the aged kidney. EC, Endothelial cell; FGF-23, Fibroblast growth factor-23; GBM, Glomerular basement membrane; PEC, Parietal Epithelial Cell; RAAS: Renin-angiotensin-aldosterone system; RBF, Renal blood flow; RAAS, Renin-angiotensin-aldosterone system; TEC, Tubular epithelial cells

Fig. 2

The mechanisms involved in the kidney tubular cell senescence. Replicative (telomere shortening) and stress-induced premature senescence in the kidney tubular cells are shown in detail. Different stimuli (ischemia/reperfusion, high glucose, radiation, UUO, cisplatin, folic acid, aristolochic acid, contrast agents, etc.) induce the TEC senescence through different pathways mainly DNA damage, increased levels of intracellular ROS, epigenetic changes, cell cycle arrest, decreased levels of klotho, mitochondrial dysfunction, impaired autophagy, and ER stress. In terms of dynamics, structure, and function, different alterations can be seen in senescent cells’ mitochondria. Mitochondria are elongated and hyperfused, mitochondrial protein leaks, and the metabolites of the TCA cycle are increased in senescent cells. Senescent cells accumulate dysfunctional mitochondria and conversely mitochondria by producing ROS and pro-inflammatory phenotype result in cellular senescence. Moreover, ATP/ADP and NAD⁺/NADH ratios, and membrane potential are decreased in senescent cells’ mitochondria. Additionally, decreased mitophagy increases dysfunctional mitochondria, producing high ROS and DAMPs. High levels of mitochondrial ROS lead to the oxidation of DNA, lipids, and proteins, causing DNA breaks, mainly at telomere regions. Activation of NF-κB (a major regulator of the SASP) by direct or indirect impact of ROS engages pro-inflammatory pathways, resulting in senescence. AMPK, AMP-activated protein kinase; ATP, Adenosine triphosphate; C/EBPα, CCAAT/enhancer-binding protein alpha; CKD, Chronic kidney disease; CTGF, Connective tissue growth factor; EMT, Epithelial–mesenchymal transition; ER: Endoplasmic reticulum; ETC, Electron transport chain; IF/TA: Interstitial fibrosis/ tubular atrophy; GRO-α, Growth regulated alpha; MCP-1, Monocyte chemoattractant protein-1; mTOR, Mammalian target of rapamycin; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; PAI-1, Plasminogen activator inhibitor-1; PGC-1α, Peroxisome proliferator–activated receptor gamma coactivator-1 alpha; ROS, Reactive oxygen species; SASP, Senescence-associated secretory phenotype; TCA, Tricarboxylic acid; TNF- α, Tumor necrosis factor; UUO, Unilateral ureteral obstruction

Fig. 3

The mechanisms involved in podocyte and endothelial cell senescence. A podocyte-specific factors (transcription factors like Grhl2) lead to aged podocyte. B Environmental, systemic, and common aging-related factors cause premature podocyte senescence via different mechanisms. C Different factors such as CKD, radiation, and high level of glucose play a critical role in the development of senescent phenotype in endothelial cells. PAI-1 as a mediator in the communication between endothelial and podocyte cells has a role in the formation of glomerular lesions in the aging process in both murine and human subjects. Within this framework, the initiation of a senescence regimen in endothelial cells proves to be indispensable. Senescent glomerular endothelial cells by expression of PAI-1 drive podocyte damage by promoting the reorganization of the F-actin cytoskeleton, decreasing the number of focal adhesions, and stimulating podocyte apoptosis and detachment. C/EBPα, CCAAT/enhancer-binding protein alpha; GBM, Glomerular basement membrane; GFR, Glomerular filtration rate; GSK3B, Glycogen Synthase Kinase 3 Beta; MQ, Macrophage; mTOR, Mammalian target of rapamycin; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; PAI-1, Plasminogen activator inhibitor-1; PD-1, Programmed cell death protein 1; ROS, Reactive oxygen species; SASP, Senescence-associated secretory phenotype; SD, Slit diaphragm; SIRT1, Sirtuin-1; TGF-β, Transforming growth factor beta Grhl2; Grainyhead-like2

Fig. 4

Potential senolytic and senophorphic agents can target different signaling pathways involved in cellular senescence. A Senolytic agents are selective killers of senescent cells. They are classified into kinase inhibitors, histone deacetylase (HDAC) inhibitors, heat shock protein 90 (HSP90) inhibitors, p53 binding inhibitors, Bcl-2 family inhibitors, and UBX0101. Senomorphics are blockers of SASP. B MSCs and their secreted factors (called secretome) can be considered senotherapeutic biofactors since they can target the main signaling pathways involved in cellular senescence. See the main text for more details. AMPK, AMP-activated protein kinase; DDR, DNA damage response; ECM, Extracellular matrix; ER, Endoplasmic reticulum; FOXO4-DRI, Fork head box O transcription factor 4-D-Retro-Inverso; HSP90, Heat shock protein 90; JAK, Janus kinase; MSCs, mesenchymal stem cells; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, Phosphoinositide 3-kinase; ROS, Reactive oxygen species; SA-β-gal, Senescence-associated beta-galactosidase; SASP, senescence-associated secretory phenotype