Renal podocyte senescence in human obesity detected by urinary extracellular vesicles

Lei Zhang; Mina Al-Saeedi; Aleksandar Denic; Kyra L Jordan; Ning Yang; Fei Yuan; Xiangyang Zhu; Ailing Xue; Hui Tang; Alfonso Eirin; Amir Lerman; Mary Fidler; LaTonya J Hickson; Andrew D Rule; Aleksandra Kukla; Lilach O Lerman

doi:10.1016/j.ebiom.2025.106116

Renal podocyte senescence in human obesity detected by urinary extracellular vesicles

EBioMedicine. 2026 Feb:124:106116. doi: 10.1016/j.ebiom.2025.106116. Epub 2026 Jan 6.

Authors

Affiliations

¹ Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; Department of Urology, Zhongda Hospital, Southeast University, Nanjing, China.
² Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; Department of Medicine, Brookdale Hospital Medical Center, Brooklyn, NY, USA.
³ Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
⁴ Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; Division of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
⁵ Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; Department of Urology, Shanghai Children's Medical Center, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
⁷ Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA.
⁸ Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL, USA.
⁹ Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA. Electronic address: Lerman.Lilach@Mayo.Edu.

Abstract

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.

Keywords: Kidney dysfunction; Obesity; Podocyte senescence; Urinary extracellular vesicles.

MeSH terms

Adult
Biomarkers / urine
Cellular Senescence*
Extracellular Vesicles* / metabolism
Female
Humans
Male
Middle Aged
Obesity* / metabolism
Obesity* / pathology
Obesity* / urine
Podocytes* / metabolism
Podocytes* / pathology

Substances

Biomarkers