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Glomerulopathic monoclonal light chains (G-LC) interact with mesangial cells (MC), resulting in alterations of mesangial homeostasis. Early signaling events control mitogenic activities and cytokine production, which in turn participate in the subsequent pathologic events. Mesangial homeostasis is affected in two very different ways, depending on whether the G-LC is from a patient with light chain deposition disease (LCDD) or light chain–related amyloidosis (AL-Am). In contrast, tubulopathic (T)-LC chains from patients with myeloma cast nephropathy do not significantly interact with MC and result in no alterations in mesangial homeostasis. Therefore, understanding early events in the monoclonal LC–MC interactions is fundamental. MC in culture were exposed to LC obtained and purified from the urine of patients with plasma cell dyscrasias and biopsy-proven renal disease, including LCDD, AL-Am, and myeloma cast nephropathy. Incubation of MC with G-LC, but not T-LC, resulted in cytoskeletal and cell shape changes, activation of platelet-derived growth factor-β (PDGF-β) and its corresponding receptor, cytoplasmic to nuclear migration of c-fos and NF-κβ signals, and production of monocyte chemoattractant protein-1 (MCP-1), as well as increased expression of Ki-67, a proliferation marker. Although NF-κβ activation was directly related to MCP-1 production, c-fos activation regulated proliferative signals and cytoskeletal changes in MC. Amyloidogenic LC were avidly internalized by the MC, whereas LCDD-LC effector targets were located at the MC surface. These cellular events are likely initiated as a result of interactions of the G-LC with yet-uncharacterized MC surface receptors. Dissecting the events taking place when G-LC interact with MC may define potential important targets for selective therapeutic manipulation to ameliorate or prevent the glomerular injury that ensues.