Role of epithelial CD74 in renal diseases

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CD74 (MHC class II invariant chain) is involved in antigen presentation, and has been identified as one of the receptors for the cytokine macrophage migration inhibitory factor (MIF). We recently showed that MIF and CD74 mediated the cross-talk between glomerular cells and drive their pathological proliferation in glomerulonephritis. In contrast, we also discovered that MIF can improve tubular cell regeneration, limit cell-cycle arrest and programmed cell death, thereby improving the course of both acute and chronic, non-immune, tubulointerstitial diseases. Our unpublished preliminary data suggest that in these tubulointerstitial diseases, CD74 is expressed de novo in renal tubular cells and that CD74 deficient mice display increased renal fibrosis and inflammation. Here we hypothesize, that CD74 has potent, cytoprotective, non-inflammatory functions that might limit progression of renal diseases. To test our hypothesis we will analyze: i) the expression of CD74 and its co-receptors in different human renal biopsies and experimental animal models focusing on its potential applicability as a kidney disease biomarker; ii) the functional consequences of CD74 neutralization in murine disease models with tubular cell injury; iii) the dependence of CD74 effects on MIF and the potential therapeutic effectiveness of specific CD74 agonists; iv) the molecular mechanisms responsible for the renoprotective effects of CD74, including cell culture experiments and unbiased omic analyses. Collectively, these experiments aim at defining a novel renoprotective molecular pathway mediated by non-inflammatory actions of CD74 in renal diseases.