Differentially expressed genes and pathways in glomeruli in light chain deposition disease – LCDD (monoclonal immunoglobulin deposition disease): opportunities for novel therapeutic interventions

The future of organ-based therapies in monoclonal light chain-associated renal diseases is centered on the utilization of techniques that can identify specific targets to inhibit initiation and/or control progression. The present study of renal biopsies of patients with light chain deposition disease in different stages of glomerular involvement using spatial transcriptomics revealed unique gene expressions and activation of cellular pathways in mesangial cells responsible for the initiation and progression of the disease processes that can be targeted pharmacologically. Among the over-expressed genes were RPL41, RPS26, ACTA2-actin protein, TNC, and TGF (transforming growth factor) β1. The RPS and RPL genes regulate ribosomal function, their increase resulting in accentuated production of proteins. TGF-β drives matrix formation by mesangial cells, TNC is the gene responsible for the tenascin-rich mesangial nodules, and ACTA2 is an actin protein gene in myofibroblastic cells (phenotypically transformed mesangial cells), resulting in increased and cytoplasmic relocalization of actin in mesangial cells, leading to surface ruffling to promote interactions of monoclonal light chains with the SORL1 receptor. The pathways activated included the eukaryotic translation initiator, the extracellular matrix/proteoglycans and organization, and the TGF-β1 signaling, all aimed at increasing the extracellular matrix in the mesangium, responsible for its nodularity. The genes and cellular pathways differed in the various stages of glomerular LCDD, emphasizing the need for designing personalized therapies based on the evaluation of renal biopsies. Additional laboratory testing using existing models of LCDDs should be utilized to prove the efficacy of the proposed targeted interventions.