Blockade of mTOR ameliorates IgA nephropathy by correcting CD89 and CD71 dysfunctions in humanized mice

IgA nephropathy (IgAN) is the most common glomerulonephritis and major cause of renal failure worldwide. Its pathogenesis involves galactose deficient IgA1-immune complexes containing soluble IgA Fc receptor (sCD89). Both IgA1 and sCD89 bind independently to the transferrin receptor (TfR1, CD71), a mesangial IgA1 receptor. Here, we hypothesize that sCD89 plays a pathogenic role in IgAN by driving a tri-partite IgA1-sCD89-CD71 complex inducing activation in situ of the mTOR (mammalian target of rapamycin) signaling pathway in mesangial cells and contributing to disease progression. mTOR inhibition may disrupt this pathogenic axis, reducing IgA1 and sCD89 deposits, modulating CD71 expression, and alleviating disease manifestations. Here, we investigated the role of sCD89 and a mTOR inhibitor using humanized mouse models of IgAN expressing CD89 and/or IgA1.

Single cell and RNAseq data were obtained from public IgAN dataset and immunostaining was performed on childhood IgAN (cIgAN) biopsies. Human mesangial cells (HMCs) stimulation by recombinant sCD89 (rsCD89) was followed by western blot analysis. Pre-clinical assays with mTOR inhibitor (Everolimus) by oral gavage were performed using young α1KI mice injected with rsCD89 for 25 days (preventive protocol) and adult α1KICD89Tg mice (treated protocol) for 75 days. Proteinuria, renal function, and circulating immune complexes (CICs) were analyzed and kidneys were harvested for histology.

RNAseq revealed increased TfR1 and mTOR expression in mesangial cells from IgAN patients. TfR1 upregulation was confirmed in cIgAN biopsies. sCD89 stimulation induced HMC TfR1 expression and phosphorylation of mTOR, Akt and S6K1. Everolimus treatment prevented or reverted mesangial IgA1 and C3 deposits and also decreased mesangial TfR1 and cell proliferation. Everolimus impaired levels of sCD89- and IgA-CIC, proteinuria, as well as renal function.

These findings highlight the critical role of the sCD89-TfR1-mTOR axis in IgAN pathogenesis and support the use of mTOR inhibitors as a novel therapeutic approach. This approach could significantly improve outcomes by slowing disease progression and minimizing the systemic toxic effects of current immunosuppressive therapies. This is particularly crucial for pediatric patients, where the only approved treatment - steroids - has severe side effects, including detrimental impacts on bone health and growth.