Monoclonal light chain-mesangial cell interactions: Early signaling eventsand subsequent pathologic effects

Glomerulopathic monoclonal light chains (G-LC) interact with mesangial cell s (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 a ffected 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 res ult in no alterations in mesangial homeostasis. Therefore, understanding ea rly events in the monoclonal LC-MC interactions is fundamental. MC in cultu re 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-d erived growth factor-beta (PDGF-beta) and its corresponding receptor, cytop lasmic to nuclear migration of c-fos and NF-kappa beta signals, and product ion of monocyte chemoattractant protein-1 (MCP-1), as well as increased exp ression of Ki-67, a proliferation marker. Although NF-kappa beta activation was directly related to MCP-1 production, c-fos activation regulated proli ferative signals and cytoskeletal changes in MC. Amyloidogenic LC were avid ly 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. Dis secting the events taking place when G-LC interact with MC may define poten tial important targets for selective therapeutic manipulation to ameliorate or prevent the glomerular injury that ensues.