#1315 Circulating extracellular vesicles: a mediator of renal tubular oxidative stress, mitochondrial Ca2+ overload and SIRT1/PGCα axis suppression in obesity

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Abstract Background and Aims Obesity is associated with an increased risk for kidney disease. Oxidative stress has been involved in the pathogenesis of kidney diseases. Extracellular vesicles (EVs) act as endocrine factors and mediate metabolic organ crosstalk. However, their roles in renal tubular damage in obesity main unknown. We intend to investigate the related mechanisms of circulating EVs in obesity-induced oxidative stress, mitochondrial Ca2+ overload and damage of renal tubular epithelial cells (RTECs). Method To construct obesity models, 4-week-old C57BL/6J male mice were treated with a high-fat diet for 18 weeks. Aiming to explore the function of EVs, plasma EVs were isolated from lean subjects (Lean-EVs) and patients with obesity (Obese-EVs). 8-week-old HFD mice received an intraperitoneal injection of GW4869 (a blockade of EVs) and RTECs were co-cultured with EVs. The generation of intracellular reactive oxygen species (ROS) was assessed by confocal microscopy using DCFH-DA staining. Mitochondrial Ca2+ content in RTECs was assessed by Fura-2 AM staining using a microplate reader. The levels of renal tubular markers KIM-1 and NGAL were assessed by qRT-PCR, Western blog(WB) analysis and immunohistochemistry. Levels of serum creatinine (sCr), blood urea nitrogen (BUN), and urinary ACR(UACR) were detected. In addition, bioinformatics analysis were also executed to pinpoint the function of SIRT1/PGC-1α in obese-related renal tubular injury, which was also confirmed by WB in vitro experiments. Results We showed that HFD mice had significantly increased sCr, BUN, UACR, and renal tubular injury markers KIM-1 and NGAL. Obese-EVs significantly increased tubular ROS generation and mitochondrial Ca2+in vitro. Moreover, the SIRT1/PGC-1α axis was downregulated in RTECs co-cultured with Obese-EVs. The blockade of Obese-EVs effectively alleviated renal tubular injury. Conclusion Obese EVs-mediated promoted oxidative stress by ROS overgeneration, mitochondrial Ca2+ overload and SIRT1/PGC-1α axis downregulation, thus exacerbating the progression of obesity-related renal tubular injury, which can emerge as a promising therapeutic avenue to treating obesity-related renal afflictions.

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