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Dual Role of Factor H–Related Protein 1 in IgA Nephropathy Kidney Injury

Year: 2025

Type: article

Abstract: Introduction IgA nephropathy (IgAN) is characterized by glomerular IgA deposition, inducing complement activation and inflammation. Previous investigations have highlighted the association of factor H (FH)-related protein 1 (FHR-1) with IgAN. Given the dual functionality of FHR-1, encompassing its "canonical function" in complement activation and "noncanonical function" in triggering inflammation, this study investigated the role of FHR-1 in IgAN-associated kidney injury. Methods In vitro experiments used IgA1-containing immune complexes (cIgA1-IC) to stimulate human mesangial cells, mimicking IgA deposition in IgAN, to explore FHR-1's interaction with impaired mesangial cells, its modulation of complement activation, and its proinflammatory impact when cocultured with monocytes. In vivo , a genetically engineered mouse model with the endogenous liver expression of human FH and FHR-5 received multiple low-dose intraperitoneal injections of Lactobacillus casei cell wall extract (LCWE)-CFA to induce IgA deposition. The nephrotoxic effects of FHR-1 and the therapeutic potential of partial FHR-1 short consensus repeat 1-2 (FHR-1 SCR1-2 ) were assessed in this model. Results Following pathogenic cIgA1-IC treatment, FHR-1 demonstrated increased binding affinity to mesangial cells. Besides, FHR-1 augmented C3c deposition on mesangial cells. Upon bound to mesangial cells, FHR-1 stimulated cocultured monocytes to secrete higher levels of inflammatory cytokines, interleukin (IL)-1β and IL-18, mediated by complement activation–induced C3a-C3aR and C5a-C5aR pathway activation, and complement-independent interaction with EMR2 on monocytes. In the murine model, intraperitoneally injected FHR-1 heightened glomerular C3 deposition, F4/80+ macrophage, and Ly6G+ neutrophils infiltration, whereas coinjection with FHR-1 SCR1-2 mitigated these effects. Conclusion FHR-1 exacerbates kidney injury in IgAN by accelerating complement activation and inflammation. FHR-1 SCR1-2 effectively attenuated FHR-1-induced inflammation, demonstrating promising therapeutic potential for IgAN.

Source: Kidney International Reports

DOI: 10.1016/j.ekir.2025.09.047