Different types of glomerulopathic light chains interact with mesangial cells using a common receptor but exhibit different intracellular trafficking patterns

Teng, Jiamin; Russell, William J.; Gu, Xia; Cardelli, James A.; Jones, M. L.; Herrera, Guillermo A.

doi:10.1038/labinvest.3700069

Cited by 111 publications

(110 citation statements)

References 28 publications

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…Soluble proteins do not accumulate on the plasma membrane. Rather, LC proteins are rapidly internalized into the cardiomyocytes without clear evidence of undergoing a membrane binding step, unlike the findings in human renal mesangial cells (15). Our experiments using endocytic inhibitors exclude any caveolin-mediated pathway for LC internalization.…”

Section: Discussioncontrasting

confidence: 58%

See 1 more Smart Citation

Cell Damage in Light Chain Amyloidosis

Argany¹,

Lin²,

Misra³

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Light chain (AL) amyloidosis is an incurable human disease characterized by the misfolding, aggregation, and systemic deposition of amyloid composed of immunoglobulin light chains (LC). This work describes our studies on potential mechanisms of AL cytotoxicity. We have studied the internalization of AL soluble proteins and amyloid fibrils into human AC16 cardiomyocytes by using real time live cell image analysis. Our results show how external amyloid aggregates rapidly surround the cells and act as a recruitment point for soluble protein, triggering the amyloid fibril elongation. Soluble protein and external aggregates are internalized into AC16 cells via macropinocytosis. AL amyloid fibrils are shown to be highly cytotoxic at low concentrations. Additionally, caspase assays revealed soluble protein induces apoptosis, demonstrating different cytotoxic mechanisms between soluble protein and amyloid aggregates. This study emphasizes the complex immunoglobulin light chain-cell interactions that result in fibril internalization, protein recruitment, and cytotoxicity that may occur in AL amyloidosis. Light chain (AL)2 amyloidosis is a protein misfolding disease characterized by extracellular deposition of immunoglobulin light chains (LC) as amyloid fibrils. LC proteins are comprised of two distinct domains: the variable (V L ) and constant (C L ) domains (also called LC full-length (FL) protein to differentiate with the V L domain). In patients with AL amyloidosis, the LC aggregate and deposit in vital organs, causing organ failure and death (1). The factors governing deposition in individual tissues are unknown. Patients with cardiac AL amyloidosis have the worst prognosis, with a median survival of less than a year (2, 3).The finding that the V L was the primary component of amyloid fibrils influenced previous biophysical studies (4,5). Recent proteomic studies have demonstrated that amyloid deposits are likely heterogeneous in nature and can be formed by FL, V L , C L , or mixtures of all types of LC fragments (6 -8). Thermodynamic studies proposed a stabilizing role for the 3C L domain in the stability and a modulating effect on fibril formation (9). Recently, our laboratory has demonstrated that the C L domain modulates the amyloid formation reaction but has no effect on the stability of the protein (10).Soluble monoclonal LC, isolated from patients with amyloidosis, can impair rat cardiomyocyte function (11) and induce apoptotic events in mouse cardiomyocytes (12, 13). Also, urinederived LC can be internalized into primary rat cardiac fibroblasts (14) and primary human renal mesangial cells (15) through a pinocytic pathway (16) or via receptor, clathrin-mediated mechanisms, respectively (15).Within the amyloid field, it is widely accepted that oligomeric species are potentially more toxic than mature fibrils (17-20). However, toxicity associated with amyloid fibrils may also be pathologically relevant. Engel et al. (21) described a mechanism in which growth of islet amyloid associated polypeptides fibrils is re...

show abstract

Section: Discussioncontrasting

confidence: 58%

“…Also, urinederived LC can be internalized into primary rat cardiac fibroblasts (14) and primary human renal mesangial cells (15) through a pinocytic pathway (16) or via receptor, clathrin-mediated mechanisms, respectively (15).…”

Section: Light Chain (Al)mentioning

confidence: 99%

Cell Damage in Light Chain Amyloidosis

Argany¹,

Lin²,

Misra³

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…These lysosomes actively engage in LC processing, as has been clearly shown in previous studies. 44 Although these HMCs express CD68 and exhibit prominent lysosomes, they are not true tissue Invasion experiments conducted showed no evidence of these cells traversing the membrane of the Boyden Chambers even after 96 h of incubation. These transformed MCs do not become motile scavengers within the mesangium, but rather remain in situ engaged in the internalization and processing of amyloidogenic LCs.…”

Section: Discussionmentioning

confidence: 92%

“…[36][37][38][39][40][41][42][43][44][45][46][47][48] Our rationale is based on the belief that different LCs can induce remarkably distinct pathophysiologic changes in the kidney. Said LCs have been classified as either tubulopathic (MCN), or glomerulopathic (AL-Am and LCDD) clearly based on the location in which their pathologic effects are evident.…”

Section: Discussionmentioning

confidence: 99%

“…Data obtained in our laboratory indicate the presence of a single cell surface receptor and the different glomerulopathic LCs compete for binding sites on this receptor. 44 LCDD-LCs are catabolized in the early endosomes, while the AL-Am-LCs have been shown to be transported to the mature lysosomes for processing ( Figure 16). Here, these amyloidogenic LCs undergo processing eventually, leading to the formation of amyloid fibrils.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

AL-amyloidosis and light-chain deposition disease light chains induce divergent phenotypic transformations of human mesangial cells

Keeling

Teng

Herrera

2004

Laboratory Investigation

Self Cite

122

View full text Add to dashboard Cite

Human mesangial cells (HMCs) are injured by either excessive amounts or abnormal light chains (LCs), or a combination of both in patients with plasma cell dyscrasias. Consequently, these HMCs undergo phenotypic transformations. HMCs were incubated with eight different light-chains (LCs) for 96 h. These cells, in addition to 51 patient samples from patients with AL-amyloidosis (AL-Am), light-chain deposition disease (LCDD), myeloma cast nephropathy (MCN) and controls were analyzed by immunohistochemistry for CD68, musclespecific actin (MSA), smooth muscle actin (SMA), CD14, and Ham56 protein expressions. All samples were also studied using electron microscopy. Greater staining (four-and three-fold) expressions of CD68 and Ham56, respectively, were observed in the HMCs incubated with AL-Am-LCs compared to those with LCDD-LCs and control. SMA expression levels were five-fold higher in LCDD-LC-treated cells compared to the other categories of LC-treated and control cells. Similar results were obtained in the renal specimens, however, CD68 levels were 12-fold higher in the AL-Am cases compared to the LCDD cases, respectively. Conversely, MSA and SMA levels were three fold higher in the LCDD cases than in the AL-Am ones. No CD14 expression was noted in any of the samples and CD-34 staining of HMCs treated with the various LCs only showed rare positive cells. The renal glomerulus is a complex structure, consisting of a number of cell types performing specialized functions, which all culminate in the filtration of plasma and the production of urine. The glomerular mesangial cell is one of the major cell types and accounts for 30-40% of the total population of the glomerulus. 1 These cells, being of mesenchyme origin, are derived from smooth muscle cell precursors and, although being able at times to perform phagocytic functions, are not from the mononuclear phagocytic (monocytic) system. Ultrastructural and morphological evidence show the glomerular mesangial cells to be similar to smooth muscle cells and express many of their associated proteins.Ultrastructurally, the mesangial cell appears to be remarkably irregular in shape with numerous processes of varying lengths projecting into the surrounding extracellular matrix (ECM) and connecting with the glomerular basement membrane (GBM). The cell generally has an indented nucleus and a small amount of cytoplasmic organelles such as mitochondria, lysosomes, ribosomes, endoplasmic reticulum and stacked Golgi cysternae. 2 Numerous bundles of small intracellular filaments with spindle densities or dense bodies and associated attachment plaques are present in the normal mesangial

show abstract

Systemic Amyloidoses

Ramı́rez-Alvarado

Buxbaum

2010

Protein Misfolding Diseases

View full text Add to dashboard Cite

Different types of glomerulopathic light chains interact with mesangial cells using a common receptor but exhibit different intracellular trafficking patterns

Cited by 111 publications

References 28 publications

Cell Damage in Light Chain Amyloidosis

Cell Damage in Light Chain Amyloidosis

AL-amyloidosis and light-chain deposition disease light chains induce divergent phenotypic transformations of human mesangial cells

Systemic Amyloidoses

Contact Info

Product

Resources

About