Glomerulopathic Light Chain-Mesangial Cell Interactions: Sortilin-Related Receptor (SORL1) and Signaling

Guillermo A Herrera; Luis Del Pozo-Yauner; Jiamin Teng; Chun Zeng; Xinggui Shen; Takahito Moriyama; Veronica Ramirez Alcantara; Bing Liu; Elba A Turbat-Herrera

doi:10.1016/j.ekir.2021.02.014

Glomerulopathic Light Chain-Mesangial Cell Interactions: Sortilin-Related Receptor (SORL1) and Signaling

Kidney Int Rep. 2021 Mar 13;6(5):1379-1396. doi: 10.1016/j.ekir.2021.02.014. eCollection 2021 May.

Authors

Affiliations

¹ Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
² Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
³ Louisiana State University, Health Sciences Center, Shreveport, Louisiana, USA.
⁴ Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan.
⁵ Mitchell Cancer Institute, College of Medicine, University of South Alabama, Mobile, Alabama, USA.

Abstract

Introduction: Deciphering the intricacies of the interactions of glomerulopathic Ig light chains with mesangial cells is key to delineate signaling events responsible for the mesangial pathologic alterations that ensue.

Methods: Human mesangial cells, caveolin 1 (CAV1), wild type (WT) ,and knockout (KO), were incubated with glomerulopathic light chains purified from the urine of patients with light chain-associated (AL) amyloidosis or light chain deposition disease. Associated signaling events induced by surface interactions of glomerulopathic light chains with caveolins and other membrane proteins, as well as the effect of epigallocatechin-3-gallate (EGCG) on the capacity of mesangial cells to intracellularly process AL light chains were investigated using a variety of techniques, including chemical crosslinking with mass spectroscopy, immunofluorescence, and ultrastructural immunolabeling.

Results: Crosslinking experiments provide evidence suggesting that sortilin-related receptor (SORL1), a transmembrane sorting receptor that regulates cellular trafficking of proteins, is a component of the receptor on mesangial cells for glomerulopathic light chains. Colocalization of glomerulopathic light chains with SORL1 in caveolae and also in lysosomes when light chain internalization occurred, was documented using double immunofluorescence and immunogold labeling ultrastructural techniques. It was found that EGCG directly blocks c-Fos cytoplasmic to nuclei signal translocation after interactions of AL light chains with mesangial cells, resulting in a decrease in amyloid formation.

Conclusion: Our findings document for the first time a role for SORL1 linked to glomerular pathology and signaling events that take place when certain monoclonal light chains interact with mesangial cells. This finding may lead to novel therapies for treating renal injury caused by glomerulopathic light chains.

Keywords: AL-amyloidosis; SORL1; caveolins; immunoglobulin light chains; light chain deposition disease; mesangial cell; receptor.