Animal Models of Light Chain Deposition Disease Provide a Better Understanding of Nodular Glomerulosclerosis.

Background: Light chain deposition disease (LCDD) is a model of glomerulosclerosis. The mature lesion of LCDD mimics nodular glomerulosclerosis in diabetic nephropathy. The pathogenetic mechanisms involved are similar in both disorders, though the causative factors are entirely different. This fact highlights the generic response of the mesangium to varied stimuli. In-vitro work has provided much insight into the pathogenesis of glomerulosclerosis in LCDD where the mesangium is the main target for initiation and progression of the disease. The lack of animal models has prevented the development of further therapeutic approaches to be tested in platforms such as ex-vivo and in-vivo preparing the way for human studies.

Methods: Light chains (LCs) obtained from the urine of patients with renal biopsy proven LCDD were delivered to glomeruli using ex-vivo and in-vivo approaches to address whether in-vitro information could be validated in-vivo. Selected in-vitro studies were conducted to address specific issues dealing with mesangial cell (MC) differentiation and composition of extracellular matrix to add additional data to the existing vast literature. Using light, electron and scanning microscopy together with immunohistochemistry and ultrastructural immunolabeling, MCs incubated in Matrigel with LCDD LCs, as well as delivery of such LCs by perfusion via renal artery (ex-vivo) and penile dorsal vein (in-vivo) to the kidneys, validation of pathogenetic pathways previously suggested in in-vitro experiments were tested and confirmed.

Results: The animal models described in this manuscript provide validation for the in-vitro data that have been previously published and expand our appreciation of the important role that caveolin-1 plays in signaling events essential for the downstream sequence of events that eventually leads to the pathological alterations centered in the mesangium characterized by an increase in matrix production and formation of mesangial nodules.

Conclusions: The same findings observed in renal biopsies of patients with LCDD (mesangial expansion with increased matrix) were documented in the ex-vivo and in-vivo platforms. In-vivo understanding of the pathogenesis of mesangial glomerulosclerosis, as accomplished in the reported research, is crucial for the design of novel therapeutic approaches to treat a number of glomerulopathies with similar pathogenetic mechanisms. Inhibiting interactions between glomerulopathic LCs and MCs or interrupting the protein production/secretion pathways are potentially effective therapeutic maneuvers. The results obtained with caveolin-1 knockout mice emphasized the importance of caveolin-1 in signaling events essential to effect downstream mesangial alterations.