Metabolomics Reveals Exosome Protection in Aging Mouse Kidneys via Ferroptosis Alleviation

TL;DR

This study shows that exosomes from stem cells help protect aging mouse kidneys by reducing harmful processes like ferroptosis and improving kidney function.

Contribution

The study identifies ferroptosis inhibition and metabolic pathway modulation as novel mechanisms for exosome-based kidney protection in aging.

Findings

hUCMSC-exos reduced blood markers of kidney damage and improved kidney structure in aging mice.

Exosome treatment inhibited ferroptosis and restored mitochondrial function in aged kidneys.

Metabolomics revealed 62 differential metabolites, including indoxyl sulfate as a potential biomarker for age-related kidney injury.

Abstract

This study evaluated the effects of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-exos) on renal function in naturally aging mice and explored underlying mechanisms. Twenty-four-month-old C57BL/6J mice were divided into a natural aging group (WT-AC, n = 10) and an hUCMSC-exos intervention group (WT-AEX, n = 10). Blood and kidney tissues were analyzed for biochemical markers, histological changes, and metabolomic profiles. hUCMSC-exos significantly reduced blood urea nitrogen, creatinine, and uric acid levels compared to the natural aging group (P < 0.01). Histological examination revealed reduced inflammatory cell infiltration, tubular degeneration, and interstitial fibrosis in the hUCMSC-exos group. Transmission electron microscopy demonstrated mitochondrial shrinkage, cristae rupture, and podocyte foot process effacement in the natural aging group, while the hUCMSC-exos group exhibited restored mitochondrial morphology, including intact cristae and reduced swelling. Aging markers (SA-β-Gal, p16INK4a, and γH2AX) were downregulated in the hUCMSC-exos group. Metabolomics identified 62 differential metabolites, with indoxyl sulfate as a potential biomarker for age-related renal injury. Enriched pathways included glutathione metabolism, glycerolipid metabolism, and aminoacyl-tRNA biosynthesis. hUCMSC-exos inhibited ferroptosis by reducing divalent iron ions and malondialdehyde levels, increasing the glutathione/oxidized glutathione ratio, and upregulating glutathione peroxidase 4 expression. These findings suggest that hUCMSC-exos improve renal function, reduce inflammation and fibrosis, and mitigate aging-related structural changes in naturally aging mice. The study highlights the protective role of hUCMSC-exos against renal aging through modulation of key metabolic pathways and ferroptosis inhibition, providing potential therapeutic targets for aging-related kidney injury.