Junyan Yu, Xiaosi Hong, Tianxin Zhu, Jiabin Lin, Yifan Du, Junru Dai, Shaoying Luo, Li Yan, Meng Ren, Kan Sun, Tingting Zeng
Diabetic nephropathy (DN) is a leading cause of end-stage renal failure, with renal tubular epithelial cell injury serving as a core pathological driver. Visceral adipose-derived stem cells (ADSCs) exhibit enhanced proliferation and secretion under diabetic hyperglycemic conditions, yet their role in DN pathogenesis remains unclear. This work investigated the protective effects and molecular mechanism of small extracellular vesicles (sEVs) secreted by high glucose (HG)-treated visceral ADSCs against tubular damage and DN progression. Rat epididymal adipose ADSCs were cultured with HG or high mannitol (HM), and HK-2 tubular cells were incubated with ADSC conditioned medium or purified sEVs to evaluate cellular apoptosis, proliferation and epithelial-mesenchymal transition (EMT). GW4869 was used to inhibit sEV release to confirm vesicle-mediated effects. In diabetic rats, tail vein administration of HG-sEVs or HM-sEVs was conducted to detect renal function, histopathological injury and fibrotic marker expression, while proteomic and bioinformatic analyses were performed to identify functional cargos within HG-sEVs. Cellular assays revealed that HG-stimulated ADSC conditioned medium suppressed EMT in HK-2 cells without altering cell apoptosis or proliferation, and GW4869 treatment abrogated this anti-EMT activity. In vivo HG-sEV intervention reduced serum Cystatin C and urinary albumin-to-creatinine ratio (UACR), mitigated renal fibrosis and lowered renal EMT levels in diabetic animals. Proteomics verified abundant FGF18 enrichment in HG-sEVs, which represses tubular EMT and collagen synthesis via inhibiting the PI3K-Akt signaling pathway. In summary, HG-induced ADSC-derived sEVs alleviate tubular EMT, relieve renal fibrosis and improve renal function in diabetic rats, and the renoprotective effect is predominantly attributed to FGF18-mediated PI3K-Akt pathway suppression.