Genetic Disorders of the Glomerular Filtration Barrier

Li, Anna S; Ingham, Jack; Lennon, Rachel

doi:10.2215/cjn.11440919

Cited by 39 publications

(25 citation statements)

References 59 publications

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“…Nephrotic syndrome can be caused by dysfunctions of podocytes, endothelial cells, or GBM, indicating that all 3 components are essential for maintaining the glomerular filtration barrier. Extensive genetic studies of nephrotic syndrome have identified mutations in genes important for establishing and maintaining the barrier (1).…”

Section: Introductionmentioning

confidence: 99%

Laminin β2 variants associated with isolated nephropathy that impact matrix regulation

Kikkawa¹,

Hashimoto²,

Takizawa³

et al. 2021

JCI Insight

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Mutations in LAMB2 , encoding laminin β 2 , cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense mutations that have been identified affect primarily the N-terminus of laminin β 2 . On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the β 2 LEa-LF-LEb domains are exclusively found in cases with isolated nephropathy. Here we report the clinical features of mild isolated nephropathy associated with 3 LAMB2 variants in the LEa-LF-LEb domains (p.R469Q, p.G699R, and p.R1078C) and their biochemical characterization. Although Pierson syndrome missense mutations often inhibit laminin β 2 secretion, the 3 recombinant variants were secreted as efficiently as WT. However, the β 2 variants lost pH dependency for heparin binding, resulting in aberrant binding under physiologic conditions. This suggests that the binding of laminin β 2 to negatively charged molecules is involved in glomerular basement membrane (GBM) permselectivity. Moreover, the excessive binding of the β 2 variants to other laminins appears to lead to their increased deposition in the GBM. Laminin β 2 also serves as a potentially novel cell-adhesive ligand for integrin α 4 β 1 . Our findings define biochemical functions of laminin β 2 variants influencing glomerular filtration that may underlie the pathogenesis of isolated nephropathy caused by LAMB2 abnormalities.

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Section: Introductionmentioning

confidence: 99%

Laminin β2 variants associated with isolated nephropathy that impact matrix regulation

Kikkawa¹,

Hashimoto²,

Takizawa³

et al. 2021

JCI Insight

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“…It has been found that immune-mediated glomerular injury involves activation of both innate and adaptive immunity, which leads to the clinical and pathological manifestation of the disease. Over the past 10 years, more than 80 genes causing glomerular barrier dysfunction have been identified [2]. With the emergence of human genetic studies, understanding which gene sequence is the main trigger for the immune system malfunction became a very powerful tool to uncover the molecular drivers of these diseases and help find potential targeted therapy.…”

Section: Integrating Genomics Transcriptomics and Proteomicsmentioning

confidence: 99%

“…Varied clinical manifestation may be due to the polymorphic gene expression in the immune system as well as at the glomerular filtration barrier site, which comprises podocytes, endothelial cells, and intervening glomerular basement membrane [2]. In addition to the multiple immune cascade pathways, underlying complex molecular and cellular processes are identified by proteomics and transcriptomics in glomerular disorders like Minimal Change Disease and focal segmental glomerulosclerosis (FSGS) [1].…”

Section: Introductionmentioning

confidence: 99%

Unraveling Primary Membranous Nephropathy Using Proteogenomic Studies

Ragy¹,

Hamilton²,

Kanigicherla³

2022

Urinary Tract Infection and Nephropathy - Insights Into Potential Relationship

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Membranous nephropathy is one of the leading causes of nephrotic syndrome in adults. The disease manifests in different forms with varying severity and outcomes range from spontaneous remission to rapid disease progression. The effects of the disease are so far best understood using conventional histopathological morphology and clinical phenotype. Being an autoimmune condition subject to a multi-hit hypothesis, the notion of underlying genetic risks is being examined in recent times. Current evidence points to significant heterogeneity in the gene expression profiles in both the immune system and at the glomerular level, with potential implications for disease management. Further proteomic and transcriptomic analysis can instruct classification, prognostication, and treatment pathways. This chapter focuses on the links identified between primary membranous nephropathy and underlying gene polymorphism, and pathways using both proteomics and transcriptomic analysis. We discuss the potential impact this could have on future management to try to minimize the patient’s immunosuppression exposure and find the most effective targeted immunosuppressive therapy.

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“…Additional proteins that maintain slit diaphragm proteins, such as CD2AP, play vital roles in GFB maintenance. Podocytes are essential in GFB function, underscored by the discovery of pathogenic mutations to proteins involved in maintaining podocyte structure that are causal to proteinuric forms of kidney disease ( Vivante and Hildebrandt, 2016 ; Li et al, 2020a ). The GBM is formed by secreted products from both podocytes and endothelial cells during glomerulogenesis ( St John and Abrahamson, 2001 ).…”

Section: The Functional Barriermentioning

confidence: 99%

Modeling the Glomerular Filtration Barrier and Intercellular Crosstalk

et al. 2021

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The glomerulus is a compact cluster of capillaries responsible for blood filtration and initiating urine production in the renal nephrons. A trilaminar structure in the capillary wall forms the glomerular filtration barrier (GFB), composed of glycocalyx-enriched and fenestrated endothelial cells adhering to the glomerular basement membrane and specialized visceral epithelial cells, podocytes, forming the outermost layer with a molecular slit diaphragm between their interdigitating foot processes. The unique dynamic and selective nature of blood filtration to produce urine requires the functionality of each of the GFB components, and hence, mimicking the glomerular filter in vitro has been challenging, though critical for various research applications and drug screening. Research efforts in the past few years have transformed our understanding of the structure and multifaceted roles of the cells and their intricate crosstalk in development and disease pathogenesis. In this review, we present a new wave of technologies that include glomerulus-on-a-chip, three-dimensional microfluidic models, and organoids all promising to improve our understanding of glomerular biology and to enable the development of GFB-targeted therapies. Here, we also outline the challenges and the opportunities of these emerging biomimetic systems that aim to recapitulate the complex glomerular filter, and the evolving perspectives on the sophisticated repertoire of cellular signaling that comprise the glomerular milieu.

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Genetic Disorders of the Glomerular Filtration Barrier

Cited by 39 publications

References 59 publications

Laminin β2 variants associated with isolated nephropathy that impact matrix regulation

Laminin β2 variants associated with isolated nephropathy that impact matrix regulation

Unraveling Primary Membranous Nephropathy Using Proteogenomic Studies

Modeling the Glomerular Filtration Barrier and Intercellular Crosstalk

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