Circulating advanced glycation end products and visceral adipose tissue-derived extracellular vesicles in renal fibrosis: evidence from population-based, animal, and cellular studies

Background: Advanced glycation end products (AGEs) are associated with impaired renal function, but the mechanisms by which chronic AGE exposure promotes renal injury and fibrosis remain incompletely understood. Given the role of visceral adipose tissue (VAT) as an endocrine and inter-organ signaling organ, we investigated whether VAT-derived extracellular vesicles (EVs) contribute to AGE-associated renal fibrosis.

Methods: Plasma CML, CEL, and MG-H1 were quantified in 2,507 community-dwelling adults. A long-term high-AGE diet model was established in female Sprague-Dawley rats for 20 months. VAT-derived EVs were isolated from control and high-AGE diet-fed rats and intravenously administered to recipient C57BL/6J mice for 8 weeks. Renal function, histopathology, renal proteomics, and molecular signaling were evaluated. The effects of AGE-exposed VAT-derived EVs (AGEs-vEVs) were further investigated in HK-2 cells, and TGF-β signaling was pharmacologically inhibited using SB431542.

Result: In the community cohort, higher plasma CEL and MG-H1 concentrations were independently associated with lower eGFR and higher serum creatinine and BUN after multivariable adjustment, whereas CML showed substantially weaker associations. Long-term high-AGE dietary exposure increased AGE accumulation in VAT and kidney and was accompanied by visceral adipose tissue dysfunction, systemic metabolic disturbance, renal dysfunction, glomerular and tubular injury, and renal fibrosis. VAT-derived EVs from high-AGE diet-fed rats exhibited increased particle abundance, and their administration to healthy recipient mice induced albuminuria, renal pathological injury, and collagen deposition in the kidney. Renal proteomic profiling identified 346 differentially expressed proteins and highlighted TGF-β signaling, extracellular matrix remodeling, and related pathways. Consistently, AGEs-vEVs activated TGF-β/Smad3 signaling and increased α-SMA, collagen I, and SERPINA3 in recipient kidneys. AGEs-vEVs were internalized by HK-2 cells and induced TGF-β/Smad3 activation and a pro-fibrotic phenotype, whereas SB431542 attenuated p-Smad3 activation and the induction of α-SMA, collagen I, and fibronectin.

Conclusion: These findings support a VAT–EV–kidney communication axis through which chronic AGE exposure is associated with renal fibrosis. VAT-derived EVs may function as inter-organ carriers of pathological signals, with activation of TGF-β/Smad3 signaling contributing to the renal pro-fibrotic response.

Keywords: Advanced glycation end products; Extracellular vesicles; Visceral adipose tissue; Renal fibrosis; TGF-β; Smad3; Kidney injury; Dietary exposure