Contribution of human smooth muscle cells to amyloid angiopathy in AL (light-chain) amyloidosis

Vora, Moiz; Kevil, Christopher G.; Herrera, Guillermo A.

doi:10.1080/01913123.2017.1349852

Cited by 10 publications

(9 citation statements)

References 51 publications

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“… 29 A cell-dependent mechanism of seeding of LC amyloid aggregation may be relevant not only in kidney, because it has been recently shown that vascular smooth muscle cells also are capable of promoting AL formation by endocytosis and endolysosomal processing of LCs. 58 In conjunction, the finding of this study, as well as those previously reported by us and others, suggest that interfering the complex mechanism triggered by the interaction of GLC with its membrane receptor in MCs, in 1 or more of the several potential target points, may be a potential therapeutic strategy in both LCDD and AL-Am. 56 Ongoing studies in our laboratory pursue that goal.…”

Section: Discussionsupporting

confidence: 82%

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

Herrera

Pozo‐Yauner

Teng

et al. 2021

Kidney International Reports

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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.

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Section: Discussionsupporting

confidence: 82%

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

Herrera

Pozo‐Yauner

Teng

et al. 2021

Kidney International Reports

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“…They are then the source of the β-amyloid found in the early stages of amyloidosis in the extracellular deposits of blood vessels. This suggests the role of smooth muscle cells in the vascular median membrane in the formation of amyloid, the presence of which is observed in the vascular walls in the systemic circulation [37,39]. It is worth noting that amyloid deposits do not occur in small capillaries, which suggests the participation of smooth muscle cells vasculature in the formation of amyloid [37].…”

Section: Symptoms Of Al Amyloidosismentioning

confidence: 96%

“…While it is known that amyloid deposits can affect both small and large arteries of the heart, kidneys, and the gastrointestinal tract and lead to dysfunction, the cellular mechanisms leading to amyloid angiopathy are not fully understood [37]. The symptoms associated with amyloid angiopathy are diverse and may take place under the forms of ischemic disease and myocardial infarction, arrhythmias, malabsorption, proteinuria, and renal failure [38].…”

Section: Symptoms Of Al Amyloidosismentioning

confidence: 99%

Physiology, Diagnosis and Treatment of Cardiac Light Chain Amyloidosis

Stelmach-Gołdyś

Zaborek-Łyczba

Łyczba

et al. 2022

JCM

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AL (light-chain) amyloidosis is a systemic disease in which amyloid fibers are formed from kappa or lambda immunoglobulin light chains, or fragments thereof, produced by a neoplastic clone of plasmocytes. The produced protein is deposited in tissues and organs in the form of extracellular deposits, which leads to impairment of their functions and, consequently, to death. Despite the development of research on pathogenesis and therapy, the mortality rate of patients with late diagnosed amyloidosis is 30%. The diagnosis is delayed due to the complex clinical picture and the slow progression of the disease. This is the type of amyloidosis that most often contributes to cardiac lesions and causes cardiac amyloidosis (CA). Early diagnosis and correct identification of the type of amyloid plays a crucial role in the planning and effectiveness of therapy. In addition to standard histological studies based on Congo red staining, diagnostics are enriched by tests to determine the degree of cardiac involvement. In this paper, we discuss current diagnostic methods used in cardiac light chain amyloidosis and the latest therapies that contribute to an improved patient prognosis.

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“…[35][36][37][38] Interestingly, a similar mechanism is at play in the genesis of amyloid deposits in vascular walls. 39 The important role that lysosomes play in amyloidogenesis has been proposed for many years starting with the seminal work of Shirahama, Cohen, and Epstein in the 1970s [40][41][42] and has subsequently been further supported by experimental animal work. 43 An important component of the pathogenesis of mesangial amyloidosis involves the loss of mesangial cells as the mesangium is replaced by amyloid.…”

Section: Pathogenesismentioning

confidence: 99%

Renal amyloidosis with emphasis on the diagnostic role of electron microscopy

Herrera

2020

Ultrastructural Pathology

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Our understanding of renal diseases with structured deposits has improved in the last two decades with the development of new diagnostic techniques that also changed the role of ultrastructural pathology in diagnostic decision-making. This review article addresses the current role of electron microscopy in the evaluation of structured deposits and discusses the impact of new developments. The diagnosis in a subset of structured deposits, amyloidosis, relies on morphologic and tinctorial characteristics at the light microscopic level. Congo red staining of tissue with demonstrable birefringence upon polarization has been regarded as the mainstay during tissue evaluation; however, there are pitfalls that must be considered, and electron microscopy remains a crucial adjunct investigative tool. Ultrastructurally the amyloid fibrils are unique with their characteristic appearance. They are randomly arranged, rigid, criss-crossing, non-branching, 7-15 nm (0.07-0.15 um) in diameter and of variable length. The morphology of fibrils is very similar in the different types of amyloidosis. By scanning electron microscopy amyloid fibrils appear artfully displayed. Immunofluorescence and immunohistochemical stains can be used to characterize the type of amyloidosis while mass spectroscopy is extremely useful in cases where typing of the amyloid using the above-mentioned techniques is difficult or equivocal.

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Contribution of human smooth muscle cells to amyloid angiopathy in AL (light-chain) amyloidosis

Cited by 10 publications

References 51 publications

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

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

Physiology, Diagnosis and Treatment of Cardiac Light Chain Amyloidosis

Renal amyloidosis with emphasis on the diagnostic role of electron microscopy

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