Mechanisms and Therapeutic Perspectives of Podocyte Aging in Podocytopathies

Abstract

Podocytes are highly specialized, terminally differentiated epithelial cells essential for maintaining the glomerular filtration barrier. Their limited regenerative capacity and high metabolic demands render them particularly susceptible to aging-related stress. Accumulating evidence indicates that podocyte aging, characterized by cellular senescence, mitochondrial dysfunction, autophagy impairment, and epigenetic alterations, significantly contributes to the pathogenesis of diverse glomerular diseases collectively termed podocytopathies. These include focal segmental glomerulosclerosis, membranous nephropathy, minimal change disease, diabetic kidney disease, and lupus nephritis. This review discusses the cellular and molecular mechanisms driving podocyte aging and explores how these alterations predispose to podocyte injury, loss, and dysfunction, ultimately culminating in podocytopathies. Furthermore, we highlight current and emerging therapeutic strategies that aim to preserve podocyte health by targeting aging-associated pathways. Understanding podocyte aging elucidates mechanisms of chronic kidney disease progression and identifies novel therapeutic strategies for age-specific interventions in podocytopathies.

Keywords: glomerulosclerosis; podocyte aging; podocytopathies; proteinuria.

Figure 1

Key pathophysiological mechanisms driving podocyte aging. Podocyte aging is a complex process characterized by several interconnected pathways. Cellular senescence manifests as irreversible cell cycle arrest, persistent DDR, and secretion of a SASP, promoting local inflammation and paracrine senescence. Mitochondrial dysfunction and oxidative stress, including impaired oxidative phosphorylation, accumulation of damaged mitochondria, excess ROS production, and mtDNA damage, compromise energy homeostasis and activate redox-sensitive stress signaling. Autophagy and lysosomal impairment lead to defective autophagosome formation, lysosomal dysfunction, and accumulation of misfolded proteins and damaged organelles, exacerbating proteotoxic stress. Epigenetic alterations, such as DNA and histone methylation, and chromatin remodeling, reshape gene expression programs that control stress responses, mitochondrial function, and cell cycle. Cytoskeletal dysregulation, particularly affecting actin filament organization, SD integrity, and adhesion to GBM, results in FPE and increased podocyte detachment. Together, these pathways converge to compromise podocyte function, reduce regenerative capacity, and drive progressive glomerular injury across diverse podocytopathies. Abbreviation: DDR: DNA damage response, SASP: senescence-associated secretory phenotype, ROS: reactive oxygen species, mtDNA: mitochondrial DNA, SD: slit diaphragm, GBM: glomerular basement membrane, FPE: foot process effacement.

Figure 2

Cross-disease map linking stimuli, signaling pathways, aging phenotypes, and podocytopathies. The first column summarizes upstream stimuli; the second shows representative signaling nodes; the third denotes convergent cellular aging phenotypes, and the last column indicates diseases. In FSGS and MCD, APOL1 risk signaling, biomechanical stress, and immune-inflammatory cues converge on cytoskeletal dysregulation and mitochondrial dysfunction. In MN, PLA2R/sPLA2-IB activates p38MAPK/mTOR, leading to ULK1 Ser757 phosphorylation and inhibition of autophagy. In LN, immune activation via CD36 and C5a/C5aR1 promotes DRP1 phosphorylation, combining autophagy impairment with mitochondrial injury. Mechanical stress sensed by Piezo1 perturbs the actin cytoskeleton in HN. Lipid overload activates NF-κB/NLRP3, driving mitochondrial dysfunction in ORG. In DKD, HG/AGEs trigger NOX4/TRPC6-dependent mtROS and mitochondrial injury; altered AKAP1, UCP2, ALCAT1, and mGPDH further compromise mitochondrial quality control, while SIRPα-induced PKM2 nuclear translocation favors aerobic glycolysis. Lipotoxic/inflammatory mediators activate NLRP3 and a SASP; TRAIL and RARRES1 promote PANoptosis/apoptosis, reinforcing podocyte senescence. In AS, COL4A3/4/5 mutations upregulate NOX4, increasing mtROS and DDR to produce oxidative stress; α-galactosidase A deficiency in Fabry nephropathy causes GL-3 accumulation and defective autophagosome–lysosome fusion, culminating in mitochondrial dysfunction. Abbreviations: APOL1: apolipoprotein L1, PLA2R: phospholipase A2 receptor, sPLA2-IB: secretory phospholipase A2 group IB, ATP: adenosine triphosphate, mTORC1: mechanistic target of rapamycin complex 1, ROS: reactive oxygen species, YAP: yes-associated protein, FAK: focal adhesion kinase, ROCK2: Rho-associated kinase 2, CTLA4: cytotoxic T-lymphocyte antigen 4, IL-18: interleukin 18, ox-LDL: oxidized low-density lipoprotein, NLRP3: NOD-like receptor family pyrin domain-containing 3, GSDMD: Gasdermin D, MAPK: mitogen-activated protein kinase, mTOR: mechanistic target of rapamycin, C5a: complement component C5a, C5aR1: C5a receptor 1, ULK1: Unc-51-like kinase 1, DRP1: dynamin-related protein 1, NOX4: NADPH oxidase 4, TRPC6: transient receptor potential canonical 6, mtROS: mitochondrial reactive oxygen species, DDR: DNA-damage response, AKAP1: A-kinase anchoring protein 1, UCP2: uncoupling protein-2, ALCAT1: acyl-CoA:lysocardiolipin acyltransferase-1, mGPDH: mitochondrial glycerol-3-phosphate dehydrogenase, SIRPα: signal regulatory protein-α, PKM2: pyruvate kinase M2, JAML: junctional adhesion molecule-like, CXCL16: C–X–C chemokine ligand 16, RARRES1: retinoic-acid-responsive 1, TRAIL: TNF-related apoptosis-inducing ligand, PANoptosis: integrated pyroptosis–apoptosis–necroptosis, SASP: senescence-associated secretory phenotype, GL-3: globotriaosylceramide, PTEN: phosphatase and tensin homolog, HG: hyperglycemia, AGEs: advanced glycation end-products, ORG: obesity-related glomerulopathy, HN: hypertensive nephropathy, MCD: minimal change disease, MN: membranous nephropathy, LN: lupus nephritis, FSGS: focal segmental glomerulosclerosis, DKD: diabetic kidney disease, AS: Alport syndrome.

Figure 3

Key molecular players driving podocyte aging in podocytopathies. A variety of key molecules are implicated in the progression of podocyte aging across multiple podocytopathies, including focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, diabetic kidney disease, lupus nephritis, Alport syndrome, Fabry disease, hypertensive nephropathy, and obesity-related glomerulopathy. These molecules contribute to distinct pathological mechanisms such as cellular senescence, mitochondrial dysfunction, impaired autophagy, epigenetic alterations, cytoskeletal dysfunction, and inflammatory responses. The molecules in red are upregulated in the disease condition, while the blue ones are downregulated. Abbreviation: C5a: complement component C5a, C5aR1: C5a receptor 1, DRP1: dynamin-related protein 1, NOX4: NADPH oxidase 4, SMPDL3b: sphingomyelin phosphodiesterase acid-like 3b, VEGFA: vascular endothelial growth factor A, DDR1: discoidin domain receptor 1, NLRP3: NOD-like receptor thermal protein domain-associated protein 3, IL-33: interleukin 33, CTLA-4: cytotoxic T-lymphocyte antigen 4, PLA2R: phospholipase A2 receptor, sPLA2-IB: secretory phospholipase A2 group IB, C5b-9: complement component 5b-9, APOL1: apolipoprotein L1 gene, mTORC1: mechanistic target of rapamycin complex 1, mTOR: mechanistic target of rapamycin, MAD2B: mitotic arrest deficient 2-like protein 2, PAR-1: protease receptor 1, CCR2: C–C chemokine receptor type 2, TRPC6: transient receptor potential canonical 6, YAP: yes-associated protein, METTL14: methyltransferase-like 14, SIRT1: sirtuin 1, FHL2: four-and-a-half LIM domains protein 2, USP22: ubiquitin-specific protease 22, SIRT2: sirtuin 2, Hsp70: heat shock protein 70, P2X7: purinergic 2X7, PTEN: phosphatase and tensin homolog, METTL3: methyltransferase-like 3, TIMP2: tissue inhibitor of metalloproteinases 2, EZH2: enhancer of zeste homolog 2, H3K27me3: histone H3 lysine 27 trimethylation, DOT1L: disruptor of telomeric silencing 1-like, RCAN1: regulator of calcineurin 1, GSK3β: glycogen synthase kinase 3 beta, SHP-1: Src homology region 2 domain-containing phosphatase-1, GPR43: G protein-coupled receptor 43, JAML: junctional adhesion molecule-like protein, CXCL16: C–X–C chemokine ligand 16, TRAIL: tumor necrosis factor (TNF)-related apoptosis-inducing ligand, RARRES1: retinoic acid receptor responder protein-1, CPT1A: carnitine palmitoyltransferase-1A, ALCAT1: acyl-coenzyme A:lyso-cardiolipin acyltransferase-1, AKAP1: A-kinase anchoring protein 1, UCP2: uncoupling proteins 2, mGPDH: mitochondrial glycerol 3-phosphate dehydrogenase, PGRN: progranulin, SIRPα: signaling regulatory protein alpha.