Glomerulopathic light chain mesangial cell interactions modulate in vitro extracellular matrix remodeling and reproduce mesangiopathic findings documented in vivo

Glomerulopathic light chains (LCs) are associated with two distinct mesangi opathies: AL (light-chain-related) amyloidosis and light-chain deposition d isease (LCDD) with immunomorphologic features that are well documented in t he literature. Even though both conditions are caused by monoclonal LCs, th ese entities differ dramatically in their morphologic expressions. In AL am yloidosis the mesangial matrix is replaced by amyloid fibrils, while in LCD D the matrix increases as a consequence of deposition of excess extracellul ar matrix (ECM). The immunomorphologic mesangial alterations observed in bi opsy material are closely reproduced in vitro when mesangial cells grown on an artificial matrix are incubated with monoclonal light chains obtained f rom the urine of patients with either condition. This article summarizes pr eviously reported data, reports new findings, and focuses on integrating al l the available information on the subject. When mesangial cells are incuba ted with LCDD-LCs, production of ECM proteins (collagen IV, laminin, fibron ectin, and tenascin) is increased, with maximum effect at 72 hours post LC treatment. A concomitant decrease in collagenase IV activity further accent uates the accumulation of mesangial matrix. These effects are mediated thro ugh transforming growth factor-beta (TGF-beta) activation. In contrast, whe n mesangial cells are incubated with Am-LCs, a decrease in ECM protein prod uction and a stimulatory effect on collagenase IV is observed, which result s in matrix degradation and facilitates amyloid deposition. The decreased T GF-beta documented in the literature in this setting precludes adequate mat rix repair. These findings substantiate the morphologic alterations observe d in renal biopsy specimens and in the in vitro model. Using this in vitro model, it is then possible to delineate the LC interactions with putative r eceptors at the mesangial cell surface that regulate mesangial cell pathobi ologic responses and mesangial matrix homeostasis.