¹Department of Pathology, Saint Louis University Health Sciences Center, Saint Louis, Missouri, USA

Correspondence: Guillermo A. Herrera, Nephrocor, 1700 N Desert Dr, Tempe, Arizona 85281, USA. E-mail: gherrrera@nephrocor.com

²Current address: Nephrocor, 1700 N Desert Dr, Tempe, Arizona 85281, USA.

Received 8 November 2007; Revised 15 July 2008; Accepted 12 August 2008; Published online 15 October 2008.

Abstract

Nodular glomerulosclerosis results from increased deposition of extracellular matrix proteins and monotypic light chains. The inability of mesangial cells to degrade abnormal levels of tenascin-C—along with the increased expression of some growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor- (TGF-)—is crucial to the pathogenesis of light chain deposition disease (LCDD). In order to study the molecular processes contributing to LCDD, we grew mesangial cells in three-dimensional matrices and incubated the cells with free light chains purified from the urine of patients with biopsy-proven LCDD, immunoglobulin-associated amyloid deposits, or myeloma cast nephropathy. Light chains of the latter two cohorts served as controls. Mesangial cells incubated with light chains from patients with LCDD show a significant increase in tenascin-C expression, centrally located within newly formed nodules, along with increased expression of PDGF and TGF-s, compared to mesangial cells incubated with control light chains. There was less extracellular MMP-7 even though its intracellular expression is markedly increased compared to the control. Addition of active MMP-7 degraded this excess tenascin-C in vitro, a process that could be prevented by an exogenous MMP inhibitor. Our in vitro model recapitulates in vivo findings in patients with LCDD, thus allowing definition of the sequential pathologic processes associated with glomerulopathic light chain interactions with mesangial cells.