Renal podocyte senescence in human obesity detected by urinary extracellular vesicles.

BACKGROUND: Obesity is a major risk factor for kidney dysfunction, with cellular senescence and senescence-associated secretory phenotype (SASP) activation contributing to early kidney injury. Urinary extracellular vesicles (uEVs) provide a non-invasive approach to assess cellular stress. We hypothesised that obesity induces podocyte senescence detectable by podocyte-derived uEVs. METHODS: We recruited 28 obese (OB) individuals and 16 healthy volunteers (HV). Of these, uEVs from 21 OB (OB-1) and 10 HV (HV-1) were analysed for tubular-derived (urat1(+), uromodulin(+), or prominin(+)) or podocyte-specific (PODXL(+)) uEVs bearing markers of senescence (p16) and SASP (MCP-1) using flow cytometry. Their correlations with metabolic and urinary renal injury markers (kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], tumour necrosis factor-alpha [TNF-α], proteinuria) were assessed. Furthermore, kidney biopsies obtained from comparable OB-2 (n = 7) and HV-2 (n = 6) subjects were examined for tissue podocyte senescence using immunofluorescence. Podocytes were also counted in a subset of HV (n = 5) and OB (n = 4) urine samples. FINDINGS: OB had elevated body mass index (BMI) but preserved kidney function. OB-1 exhibited significantly elevated P16(+)MCP-1(+)PODXL(+) uEVs fractions compared to HV-1, which correlated with metabolic dysfunction (BMI, insulin resistance) and renal injury markers. Tubular-derived uEVs showed no differences between the groups. Kidney biopsies confirmed increased podocyte senescence (P16(+) PODXL(+) immunoreactivity) in OB-2 vs. HV-2, and numbers of urinary podocytes increased in OB. INTERPRETATION: Human obesity induces in persons with normal kidney function podocyte senescence, which is detectable non-invasively by uEVs. FUNDINGS: This study was partly supported by NIH grant numbers: DK120292, DK122734, HL158691, AG062104 (all LOL), and AG076537 (LJH). KDIGO provided support to Dr. Kukla to the 2024 Obesity and Chronic Kidney Disease Controversies Conference.