hUCMSC-Exos alter renal injury markers, gut microbiota, and `NLRP3` inflammasome signaling in IgA nephropathy mice

IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally and a leading cause of end-stage kidney disease, yet effective disease-specific therapies remain scarce. Current treatments often fall short in addressing the underlying pathology. Growing evidence points to gut microbiota dysbiosis and aberrant innate immune activation, particularly involving the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome pathway, as key drivers in IgAN pathogenesis. This study investigated whether human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) could modulate these critical parameters in IgAN.

Researchers isolated hUCMSC-Exos and administered them to an IgAN-like mouse model. The study assessed renal function, histopathological changes, and systemic inflammatory markers in these mice. Gut microbiota composition was meticulously analyzed using 16S rRNA sequencing, and exploratory microbial co-occurrence networks were constructed to identify key microbial interactions. In vitro, podocytes stimulated with galactose-deficient IgA1 (Gd-IgA1) were exposed to exosomes to evaluate inflammasome-related markers. Additionally, transcriptomic data from human IgAN glomeruli (GSE93798) were analyzed to explore inflammatory and immune-related gene signatures, providing translational context.

Administration of hUCMSC-Exos was associated with significant changes in renal injury markers in the IgAN-like mice, alongside notable alterations in their gut microbial composition. Microbiome analysis revealed a beneficial shift toward a microbial profile more closely resembling that of control animals. This shift included the enrichment of specific bacterial taxa, such as Anaerostipes, Dorea, and Ruminococcus, which have previously been linked to gut metabolic homeostasis in other cohorts. These identified taxa showed strong correlations with indicators of renal dysfunction and various inflammatory markers, and were pinpointed as hub taxa within an exploratory co-occurrence network, suggesting their central role in the observed effects. > Transcriptomic analysis of human IgAN glomeruli further supported these findings, revealing altered expression of NLRP3 inflammasome-related genes and components of the aryl hydrocarbon receptor (AhR)-related signaling pathway, indicating a modulation of inflammatory activity.