PRDM16 as a Molecular Target for Delaying Podocyte Aging and Glomerulosclerosis

Background: Podocytes are essential components of the glomerular filtration barrier, and their irreversible structural and functional decline is a major contributor to glomerulosclerosis and age-related kidney disease progression. Although cellular senescence is recognized as a key driver of renal aging, the molecular mechanisms governing podocyte senescence remain poorly defined. PRDM16, a transcriptional regulator involved in cell differentiation and metabolic regulation, is hypothesized to play a critical role in the process. Methods: We utilized naturally aged mice, podocyte-specific PRDM16 conditional knockout mice (PRDM16^flox/NPHS2^Cre), and a renal cortical PRDM16 overexpression model. In vitro, podocyte senescence was induced in immortalized human podocytes by X-ray or doxorubicin. PRDM16 expression patterns and their functional consequences were assessed using SA-β-Gal staining, qRT-PCR, Western blotting, immunofluorescence, and electron microscopy. Mechanistic analyses included co-immunoprecipitation and mass spectrometry. Results: In aged mice, PRDM16 expression in podocytes was significantly reduced, correlating with increased injury. Senescent podocytes in vitro exhibited decreased PRDM16 expression, elevated γ-H2AX levels, and enhanced SA-β-Gal activity. Overexpression of PRDM16 alleviated the senescence phenotype and restored podocyte marker expression, while PRDM16 knockdown aggravated cellular damage. In vivo, PRDM16 overexpression in aged mouse kidneys reduced proteinuria, improved foot process architecture, and mitigated glomerulosclerosis. Conversely, podocyte-specific PRDM16 deletion led to worsened renal function and structure. Mechanistically, PRDM16 interacted with histone deacetylase 2 (HDAC2), enhancing H3K9 acetylation and activating transcription of the autophagy gene ATG4A, thereby restoring autophagic flux and delaying senescence. Conclusion: PRDM16 plays a protective role in podocyte senescence, with its expression closely linked to podocyte integrity and aging. By promoting ATG4A-mediated autophagy through epigenetic regulation, PRDM16 mitigates senescence and glomerular damage. These findings suggest PRDM16 as a novel molecular marker of podocyte aging and a promising target for therapeutic intervention in age-related kidney disease.