Senescent Podocytes in Human Obesity Release Urinary Extracellular Vesicles (uEVs)

Background: Obesity induces cellular senescence, which is implicated in renal disease progression. Senescent cells are characterized by the expression of senescence markers like P19, a cyclin-dependent kinase inhibitor, and possibly pro-inflammatory monocyte chemoattractant protein (MCP)-1. However, whether podocytes marked by podocalyxin (Podxl)+ undergo senescence in obesity is unclear. We hypothesized that patients with obesity show elevated levels of P19+/Podxl+/MCP1+ uEVs suggestive of podocyte senescence Methods: Blood and urine samples were collected from 21 obese (OB) and 10 lean subjects for uEVs quantification (NanoSight) and characterization (Flow Cytometry) for P19, Podoxl, and MCP1 expression (Fig1). Their fraction out of total uEVs was correlated with body mass index (BMI), urinary protein, kidney injury molecule (KIM)-1, and insulin levels Results: OB subjects had elevated BMI but preserved renal function (Table). The total uEV number was similar in OB and lean, but the fractions of P19+/Podxl+ and P19+/Podoxl+/MCP1+ uEVs were higher in OB and directly correlated with BMI. P19+/Podoxl+/MCP1+ uEVs also correlated with urine protein, KIM1, and insulin levels (Fig2) Conclusion: Senescent podocytes in obese subjects with preserved renal function shed uEVs in proportion to obesity severity. The uEVs fraction shed by a subset of inflamed (MCP1+) senescent podocytes further correlates with renal injury markers. These may serve as early markers of glomerular senescence and guide the management of patients with obesity Funding: NIDDK Support - NIDDK Support, NIDDK SupportTable. Demographics - Parameter Lean OB Age, Yrs. 47±15 48±12 Sex, M/F 3/7 7/14 BMI, Kg/m2 25±1 44±6* Serum Creatinine, mg/dl 0.9(0.7,1.2) 0.8(0.6,1.4) eGFR, ml/min/1.73m2 90±10 96±17 Urine Protein, mg/mmol 32(2,57) 66(3,189) Mean ± SD or median (min, max) *P<0.05 vs. Lean