Complement Factor H Regulates a Complement-Extracellular Vesicle-Macrophage Axis in Immune Mediated Kidney Injury

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Introduction: Complement Factor H (FH) regulates the alternative complement pathway, and FH deficiency promotes complement activation, macrophage recruitment, and renal injury. Extracellular vesicles (EVs) mediate intercellular communication and may provide molecular signatures of tissue inflammation.Methods: We examined complement- and macrophage-associated transcriptional signatures in renal tissue and serum-, kidney-, and urine-derived EVs using a FH-deficient murine model of chronic serum sickness. Pilot kidney microarray analysis was combined with qRT-PCR and EV transcript profiling.Results: FH deficiency increased renal expression of macrophage-associated inflammatory genes, including AIF1, MMP9, S100A10, and CD44, and the complement receptor C3aR1. EVs from FH-deficient mice lacked FH transcripts and exhibited increased complement- and macrophage-associated transcripts across serum-, kidney-, and urine-derived EV populations. EV transcriptional profiles paralleled inflammatory gene expression observed in renal tissue.Discussion: FH deficiency-associated complement dysregulation produces coordinated inflammatory transcriptional signatures detectable in both kidney tissue and EVs. The concordance between intrarenal inflammatory programs and EV cargo suggests that EVs may reflect complement-mediated renal immune activity. In particular, urinary EVs may provide a non-invasive source of molecular information and potential biomarkers of complement-mediated kidney inflammation.

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