Dysregulated Renal Microcirculation in Human Obesity Detected by Urinary Extracellular Vesicles (uEVs)

Background: Obesity may dysregulate angiogenesis, and renal inflammation may induce microvascular proliferation. Plasmalemmal vesicle-associated protein (PLVAP) is a peritubular capillaries (PTC) marker, and the notch ligand pathway delta-like ligand-4 (DLL4) is a microvascular metabolic sensor that regulates angiogenesis, but their role in the kidney in obesity is undetermined. We hypothesized that human obesity dysregulates the renal microcirculation, detectable by elevated urinary levels of renal endothelial cell-derived PLVAP+/DLL4+ uEVs Methods: Blood and urine samples were prospectively collected from obese patients (OB, n=22) and lean kidney donors (n=11). uEVs were quantified and characterized for CD31, PLVAP, CD144, and DLL4 expression and their relationship with body mass index (BMI), insulin, and plasma angiopoietin levels. PTCs were also counted in time-0 biopsies of OB (n=20) and lean (n=17) kidney donors Results: OB patients had preserved renal function and elevated insulin levels(Table). The total uEV number was similar, but the fraction of CD31-/PLVAP+/CD144-/DLL4+ uEVs was higher in OB and directly correlated with BMI, plasma angiopoietin, and insulin levels (Fig1). Congruently, PTC density and count/tubule were higher in OBs than lean(Fig2) Conclusion: Obese patientsshow elevated urinary markers of renal PTC proliferation that correlate with obesity severity. These may aim to support tubular enlargement and indicate the development of early microvascular kidney injury that might be useful in the risk stratification of obese patients Funding: NIDDK Support - NIDDK Support, NIDDK SupportDemographics - Parameter Lean OB Age, Yrs. 47±15 48±12 Sex, M/F 4/7 7/15 BMI, Kg/m2 25±2 38±11* Serum Creatinine, mg/dl 0.9±0.2 0.8±0.2 eGFR, ml/min/1.73m2 90±9 98±18 Insulin, mU/l 5(2,25) 14(3,50)* mean±SD or median(min,max)*P<0.05 vs.lean