Glomerular Proteinuria: A Complex Interplay Between Unique Players

Garg, Puneet; Rabelink, Ton J.

doi:10.1053/j.ackd.2011.06.001

Cited by 31 publications

(27 citation statements)

References 111 publications

(90 reference statements)

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“…Similar associations also were evident in studies of HIV-infected individuals [19-22]. While it is possible that residual confounding from common risk factors that are shared between patients with both cardiovascular and kidney disease could contribute to these associations, this relationship also may imply common pathogenic mechanisms underlying both disease processes [27, 28]. One such common mechanism may involve disruption of the glycocalyx lining that is present on all endovascular cells, including fenestrated glomerular cells, which limits endothelial activation by preventing leukocyte and platelet adhesion while also preventing negatively charged proteins including albumin to escape from the capillary lumen.…”

Section: Discussionsupporting

confidence: 61%

Proteinuria is Associated With Neurocognitive Impairment in Antiretroviral Therapy Treated HIV-Infected Individuals

Kalayjian

Evans

et al. 2014

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background Proteinuria is a marker of vascular dysfunction that predicted increased cardiovascular mortality, and was associated with neurocognitive impairment (NCI) in population-based studies. We examined associations between proteinuria and HIV-associated NCI. Methods Multivariable logistic regression was used to examine associations between NCI at the first neurocognitive assessment (baseline) and simultaneous, clinically significant proteinuria (as random spot urine protein-to-creatinine ratios [UP/Cr] ≥ 200 mg/g) in a prospective multicenter observational cohort study. Generalized estimating equations were used to examine associations between baseline proteinuria and subsequent NCI among subjects without NCI at baseline. NCI was defined as a z-score, derived from the combination of normalized scores from the Trailmaking A & B and the Wechsler Adult Intelligence Scale-Revised Digit Symbol tests. Results 1,972 subjects were included in this analysis. Baseline proteinuria was associated with increased odds of NCI (OR: 1.41 [95% C.I., 1.08 to 1.85]; P=0.01), and with subsequent NCI among subjects without NCI at baseline (OR=1.39 [95% C.I., 1.01 to 1.93], P=0.046) in multivariable models adjusted for risk factors and potential confounders. Similar associations were evident when these analyses were limited to visits at which time study subjects maintained plasma HIV RNA levels < 200 copies/mL. Conclusions The association between proteinuria and NCI observed in this study adds to a growing body of evidence implicating contributions by vascular disease to NCI in antiretroviral treated individuals. Studies examining interventions that improve vascular function are warranted.

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Section: Discussionsupporting

confidence: 61%

Proteinuria is Associated With Neurocognitive Impairment in Antiretroviral Therapy Treated HIV-Infected Individuals

Kalayjian

Evans

et al. 2014

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…In vitro studies have shown that engagement of the nephrin extracellular domain results in Src family kinase Fyn-dependent tyrosine phosphorylation of the nephrin cytoplasmic domain (6,9,10). Phosphorylated nephrin then recruits the Src homology 2 (sh2) domain-containing proteins Nck1/Nck2, the p85 subunit of phosphatidylinositol 3-kinase (PI3K), and Crk (3)(4)(5)(6)11) and other components of the actin polymerization complex (2,3,5,12,13). Mice with the Src family kinase Fyn deleted develop proteinuria and foot process defects that are evident at 7 weeks of age (10,14).…”

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confidence: 99%

Shp2 Associates with and Enhances Nephrin Tyrosine Phosphorylation and Is Necessary for Foot Process Spreading in Mouse Models of Podocyte Injury

Verma

Venkatareddy

Kalinowski

et al. 2016

Molecular and Cellular Biology

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bIn most forms of glomerular diseases, loss of size selectivity by the kidney filtration barrier is associated with changes in the morphology of podocytes. The kidney filtration barrier is comprised of the endothelial lining, the glomerular basement membrane, and the podocyte intercellular junction, or slit diaphragm. The cell adhesion proteins nephrin and neph1 localize to the slit diaphragm and transduce signals in a Src family kinase Fyn-mediated tyrosine phosphorylation-dependent manner. Studies in cell culture suggest nephrin phosphorylation-dependent signaling events are primarily involved in regulation of actin dynamics and lamellipodium formation. Nephrin phosphorylation is a proximal event that occurs both during development and following podocyte injury. We hypothesized that abrogation of nephrin phosphorylation following injury would prevent nephrin-dependent actin remodeling and foot process morphological changes. Utilizing a biased screening approach, we found nonreceptor Src homology 2 (sh2) domain-containing phosphatase Shp2 to be associated with phosphorylated nephrin. We observed an increase in nephrin tyrosine phosphorylation in the presence of Shp2 in cell culture studies. In the human glomerulopathies minimal-change nephrosis and membranous nephropathy, there is an increase in Shp2 phosphorylation, a marker of increased Shp2 activity. Mouse podocytes lacking Shp2 do not develop foot process spreading when subjected to podocyte injury in vivo using protamine sulfate or nephrotoxic serum (NTS). In the NTS model, we observed a lack of foot process spreading in mouse podocytes with Shp2 deleted and smaller amounts of proteinuria. Taken together, these results suggest that Shp2-dependent signaling events are necessary for changes in foot process structure and function following injury. P odocytes are highly differentiated epithelial cells with membrane extensions that arborize over the basement membrane in a highly polarized manner. The terminal branches of these actin-rich membrane extensions, called foot processes, interdigitate with each other, forming specialized intercellular junctions called slit diaphragms. Podocytes undergo flattening of the foot processes, or effacement, in most forms of glomerular diseases that present with protein leaks in the urine. Foot process effacement correlates with failure of the filtration barrier and development of proteinuria in both human diseases and animal models of podocyte dysfunction. The strong correlation between foot process morphological changes and failure of the filtration barrier suggests that prevention or reversal of effacement would be beneficial.Nephrin is a transmembrane protein of the immunoglobulin superfamily that is located at the slit diaphragm (1). Nephrin's ability to regulate actin dynamics in a phosphorylation-dependent manner has been demonstrated by us and other investigators (2-6). A critical role for nephrin is suggested by the lack of normal foot process development in mice lacking nephrin or humans born with nephrin mutations ...

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“…The development of albuminuria in experimental models of diabetes is associated with changes in the glycocalyx, including loss of GAGs (12), which may occur due to hyperglycemia-induced disruption of GAG synthesis (21). Damage to any of the three layers of the GFB (endothelium, GBM, or podocyte) can result in the presence of high molecular weight proteins in the urine (22). However, because changes in component of the GFB often affect the other elements, the contribution of each individual component to the filtration barrier is not easy to discern (22).…”

Section: Glomerular Endothelial Cells: Adapted For Selective Permeabimentioning

confidence: 99%

“…Damage to any of the three layers of the GFB (endothelium, GBM, or podocyte) can result in the presence of high molecular weight proteins in the urine (22). However, because changes in component of the GFB often affect the other elements, the contribution of each individual component to the filtration barrier is not easy to discern (22). Additionally, even in health, a significant amount of albumin may pass through the GFB and be retrieved by the proximal tubule, mediated by the neonatal Fc receptor, FcRn (19,23).…”

Section: Glomerular Endothelial Cells: Adapted For Selective Permeabimentioning

confidence: 99%

The Players: Cells Involved in Glomerular Disease

Kitching

Hutton

2016

CJASN

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Glomerular diseases are common and important. They can arise from systemic inflammatory or metabolic diseases that affect the kidney. Alternately, they are caused primarily by local glomerular abnormalities, including genetic diseases. Both intrinsic glomerular cells and leukocytes are critical to the healthy glomerulus and to glomerular dysregulation in disease. Mesangial cells, endothelial cells, podocytes, and parietal epithelial cells within the glomerulus all play unique and specialized roles. Although a specific disease often primarily affects a particular cell type, the close proximity, and interdependent functions and interactions between cells mean that even diseases affecting one cell type usually indirectly influence others. In addition to those cells intrinsic to the glomerulus, leukocytes patrol the glomerulus in health and mediate injury in disease. Distinct leukocyte types and subsets are present, with some being involved in different ways in an individual glomerular disease. Cells of the innate and adaptive immune systems are important, directing systemic immune and inflammatory responses, locally mediating injury, and potentially dampening inflammation and facilitating repair. The advent of new genetic and molecular techniques, and new disease models means that we better understand both the basic biology of the glomerulus and the pathogenesis of glomerular disease. This understanding should lead to better diagnostic techniques, biomarkers, and predictors of prognosis, disease severity, and relapse. With this knowledge comes the promise of better therapies in the future, directed toward halting pathways of injury and fibrosis, or interrupting the underlying pathophysiology of the individual diseases that lead to significant and progressive glomerular disease.

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Glomerular Proteinuria: A Complex Interplay Between Unique Players

Cited by 31 publications

References 111 publications

Proteinuria is Associated With Neurocognitive Impairment in Antiretroviral Therapy Treated HIV-Infected Individuals

Proteinuria is Associated With Neurocognitive Impairment in Antiretroviral Therapy Treated HIV-Infected Individuals

Shp2 Associates with and Enhances Nephrin Tyrosine Phosphorylation and Is Necessary for Foot Process Spreading in Mouse Models of Podocyte Injury

The Players: Cells Involved in Glomerular Disease

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