What Is the Glomerular Ultrafiltration Barrier?

Fissell, William H.; Miner, Jeffrey H.

doi:10.1681/asn.2018050490

Cited by 61 publications

(47 citation statements)

References 13 publications

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“…However, both theory and evidence indicate that the GBM confers permselectivity, though likely not entirely independent of podocytes. 20,[41][42][43] Lamb2 À/À mice exhibit proteinuria preceding effacement in the first 7 days of life, 20 suggesting that the GBM is intrinsically permselective. Throughout the second month of life Del44 foot processes were widened, but they otherwise maintained the typical vertical foot process shape perpendicular to the GBM, with obvious slit diaphragms despite heavy proteinuria.…”

Section: Discussionmentioning

confidence: 99%

A deletion in the N-terminal polymerizing domain of laminin β2 is a new mouse model of chronic nephrotic syndrome

Funk

Bayer

McKee

et al. 2020

Kidney International

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The importance of the glomerular basement membrane (GBM) in glomerular filtration is underscored by the manifestations of Alport and Pierson syndromes, caused by defects in type IV collagen a3a4a5 and the laminin b2 chain, respectively. Lamb2 null mice, which model the most severe form of Pierson syndrome, exhibit proteinuria prior to podocyte foot process effacement and are therefore useful for studying GBM permselectivity. We hypothesize that some LAMB2 missense mutations that cause mild forms of Pierson syndrome induce GBM destabilization with delayed effects on podocytes. While generating a CRISPR/Cas9-mediated analogue of a human LAMB2 missense mutation in mice, we identified a 44-amino acid deletion (LAMB2-Del44) within the laminin N-terminal domain, a domain mediating laminin polymerization. Laminin heterotrimers containing LAMB2-Del44 exhibited a 90% reduction in polymerization in vitro that was partially rescued by type IV collagen and nidogen. Del44 mice showed albuminuria at 1.8-6.0 g/g creatinine (ACR) at one to two months, plateauing at an average 200 g/g ACR at 3.7 months, when GBM thickening and hallmarks of nephrotic syndrome were first observed. Despite the massive albuminuria, some Del44 mice survived for up to 15 months. Blood urea nitrogen was modestly elevated at seven-nine months. Eight to nine-month-old Del44 mice exhibited glomerulosclerosis and interstitial fibrosis. Similar to Lamb2 À/À mice, proteinuria preceded foot process effacement. Foot processes were widened but not effaced at one-two months despite the high ACRs. At three months some individual foot processes were still observed amid widespread effacement. Thus, our chronic model of nephrotic syndrome may prove useful to study filtration mechanisms, long-term proteinuria with preserved kidney function, and to test therapeutics.

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Section: Discussionmentioning

confidence: 99%

A deletion in the N-terminal polymerizing domain of laminin β2 is a new mouse model of chronic nephrotic syndrome

Funk

Bayer

McKee

et al. 2020

Kidney International

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“…The kidney eliminates metabolites, toxins, and electrolytes from the human body through a glomerular filtration barrier consist of a fenestrated endothelium, basement membrane, and podocytes ( Bartlett et al, 2016 ; Fissell and Miner, 2018 ). Proteinuria caused by glomerular filtration barrier structure changes is the hallmark of DN, which include reduced endothelial fenestrations, thickened GBM, and podocyte loss ( Satchell, 2012 ).…”

Section: The Role Of Vegf-a In Abnormal Angiogenesis Of Dnmentioning

confidence: 99%

Role of VEGF-A and LRG1 in Abnormal Angiogenesis Associated With Diabetic Nephropathy

et al. 2020

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Diabetic nephropathy (DN) is an important public health concern of increasing proportions and the leading cause of end-stage renal disease (ESRD) in diabetic patients. It is one of the most common long-term microvascular complications of diabetes mellitus that is characterized by proteinuria and glomerular structural changes. Angiogenesis has long been considered to contribute to the pathogenesis of DN, whereas the molecular mechanisms of which are barely known. Angiogenic factors associated with angiogenesis are the major candidates to explain the microvascular and pathologic finds of DN. Vascular endothelial growth factor A (VEGF-A), leucine-rich α-2-glycoprotein 1, angiopoietins and vasohibin family signal between the podocytes, endothelium, and mesangium have important roles in the maintenance of renal functions. An appropriate amount of VEGF-A is beneficial to maintaining glomerular structure, while excessive VEGF-A can lead to abnormal angiogenesis. LRG1 is a novel pro-angiogenic factors involved in the abnormal angiogenesis and renal fibrosis in DN. The imbalance of Ang1/Ang2 ratio has a role in leading to glomerular disease. Vasohibin-2 is recently shown to be in diabetes-induced glomerular alterations. This review will focus on current understanding of these angiogenic factors in angiogenesis and pathogenesis associated with the development of DN, with the aim of evaluating the potential of anti-angiogenesis therapy in patients with DN.

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“…The latter are terminally differentiated, post-mitotic epithelial cells, which induce fenestrae formation within endothelial cells by secreting VEGF, maintain the GBM and act as outer cellular layer compressing the GBM and counteracting the filtration pressure to prevent the passage of macromolecules 1,3 . Podocytes exhibit primary and secondary foot processes and enwrap the glomerular capillaries completely.…”

Section: Introductionmentioning

confidence: 99%

Par3A and Par3B orchestrate podocyte architecture by regulating RhoA levels

Koehler

Odenthal

Jess

et al. 2020

Preprint

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Glomerular diseases are a major cause for chronic kidney disorders. In the majority of cases podocyte injury is causative for disease development. Cytoskeletal rearrangements and morphological changes are hallmark features of podocyte injury and result in dedifferentiation and subsequent loss of podocytes. Here, we establish a link between components of the Par3 polarity complex and actin regulators, which are necessary to establish and maintain the podocytes architecture utilizing both, mouse and Drosophila models. We demonstrate that the two mammalian Par3 proteins, Par3A and Par3B, share redundant functions despite differing in their ability to interact with other components of the Par complex. Only simultaneous inactivation of both Par3 proteins causes a severe disease phenotype in mouse podocytes by regulating Rho-GTP levels involving the actin regulators Synaptopodin and CD2AP in an aPKC independent manner.

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What Is the Glomerular Ultrafiltration Barrier?

Cited by 61 publications

References 13 publications

A deletion in the N-terminal polymerizing domain of laminin β2 is a new mouse model of chronic nephrotic syndrome

A deletion in the N-terminal polymerizing domain of laminin β2 is a new mouse model of chronic nephrotic syndrome

Role of VEGF-A and LRG1 in Abnormal Angiogenesis Associated With Diabetic Nephropathy

Par3A and Par3B orchestrate podocyte architecture by regulating RhoA levels

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