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Nephrotic Syndrome: Components, Connections, and Angiopoietin-Like 4–Related Therapeutics

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Nephrotic Syndrome: Components, Connections, and Angiopoietin-Like 4–Related Therapeutics BRIEF REVIEW www.jasn.org Nephrotic Syndrome: Components, Connections, and Angiopoietin-Like 4–Related Therapeutics Camille Macé and Sumant S. Chugh Glomerular Disease Therapeutics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama ABSTRACT Nephrotic syndrome is recognized by the presence of proteinuria in excess of 3.5 g/24 podocin for FSGS4). These genes are h along with hypoalbuminemia, edema, hyperlipidemia (hypertriglyceridemia and best viewed as disease-related genes, hypercholesterolemia), and lipiduria. Each component has been investigated individ- with proteinuria being a major compo- ually over the past four decades with some success. Studies published recently have nent of the associated disease. Others started unraveling the molecular basis of proteinuria and its relationship with other were discovered through mutagenesis components. We now have improved understanding of the threshold for nephrotic- studies in mice (e.g., neph1).5,6 In most range proteinuria and the pathogenesis of hypertriglyceridemia. These studies reveal cases, these genes do not single-handedly that modifying sialylation of the soluble glycoprotein angiopoietin-like 4 or changing explain the development of proteinuria. key amino acids in its sequence can be used successfully to treat proteinuria. Treatment Transcriptional factors, like WT1, came strategies on the basis of fundamental relationships among different components of into light from a combination of genet- nephrotic syndrome use naturally occurring pathways and have great potential for ics7 and animal model8 studies, whereas future development into clinically relevant therapeutic agents. the role of ZHX proteins was discovered through differential gene expression J Am Soc Nephrol 25: 2393–2398, 2014. doi: 10.1681/ASN.2014030267 studies in animal models.2,9 Among po- docyte-secreted proteins implicated in human disease, the roles of angiopoietin- Nephrotic syndrome is a hallmark of glo- about each component and then consider like 4 (Angptl4) and vascular endothelial merular disease and characterized by the what remains to be investigated. Next, mo- growth factor in proteinuria were estab- presence of proteinuria in excess of 3.5 g/24 lecular connections, if known, between lished through the study of experimental h, hypoalbuminemia, and variable amounts proteinuria and the other components models.10–12 A hyposialylated form of of hyperlipidemia (hypertriglyceridemia will be discussed. Finally, novel therapeutic Angptl4 secreted from podocytes is di- and hypercholesterolemia), lipiduria, and strategies derived from the study of ne- rectly implicated in the pathogenesis edema1 (Figure 1). In children, nephrotic- phrotic syndrome will be outlined. of proteinuria in MCD and accounts range proteinuria is defined by urinary for most of the cardinal manifestations protein excretion rates .40 mg/h per of this disease, including glucocorticoid meter2. Patients with primary glomeru- PROTEINURIA sensitivity, selective proteinuria, loss lar diseases (e.g., minimal change disease of glomerular basement membrane [MCD], FSGS, and membranous ne- Several genes expressed in podocytes (GBM) charge, and classic morphologic phropathy) and systemic disorders (e.g., have now been directly or indirectly changes.1,11 Despite demonstration that diabetes mellitus, systemic lupus erythe- implicated in the pathogenesis of pro- loss of GBM charge in MCD is caused by matosis, and amyloidosis) can present teinuria. They can be classified as slit binding of Angptl4, it is not known with nephrotic syndrome. The principle diaphragm-related, cell matrix interface– driving force in nephrotic syndrome is related, cytoskeleton-related, podocyte Published online ahead of print. Publication date proteinuria, because other components surface proteins, transcriptional factors, available at www.jasn.org. develop only after proteinuria reaches a and podocyte-secreted proteins.2 Many certain threshold. Substantial research ef- of the structural proteins among these Correspondence: Dr.SumantS.Chugh,University of Alabama at Birmingham Division of Nephrology, fort has been committed to understanding categories were discovered when screen- THT 611L, 1900 University Boulevard, Birmingham, the pathogenesis of each individual com- ing for mutations in patients with disease AL 35294. Email: [email protected] ponent. The purpose of this review is to (e.g., nephrin for congenital nephrotic Copyright © 2014 by the American Society of discussinbroadtermswhatisunderstood syndrome of the Finnish type3 and Nephrology J Am Soc Nephrol 25: 2393–2398, 2014 ISSN : 1046-6673/2511-2393 2393 BRIEF REVIEW www.jasn.org diuretic efficacy, transporters in the thick ascending loop of Henle, distal tubule, collecting duct, and proximal tubule have been targeted to reduce edema. Re- cent studies suggest that the proteolytic ac- tivation of collecting duct epithelial sodium channel may be mediated by plasmin con- verted from filtered plasminogen.17,18 Treatment of edema with albumin infu- sions is generally not practiced, except in selected cases of refractory anasarca. Perhaps the least understood part of edema is increased peripheral capillary permeability, and no current therapy targets this aspect. This area has tremen- dous potential for investigation, and mechanistic studies may reveal useful clues for treating patients with refrac- tory edema. Investigating the explosive onset of edema in MCD could provide insight into additional molecular mech- anisms in nephrotic syndrome, because Figure 1. The nephrotic syndrome tree is shown. The trunk depicts increasing proteinuria, there is a potential for glomerular or pe- and the branches represent other components that appear when proteinuria crosses the ripherally secreted proteins in the path- nephrotic-range threshold. ogenesis of this phenomenon. whether complex interaction of this pro- secreting proteins into the circulation. HYPERCHOLESTEROLEMIA tein with heparan sulfate proteoglycans Angptl4 is the first of several such pro- and other GBM proteins or actual loss teins that are likely to be identified in the Nephrotic patients have elevated total of GBM charge is responsible for protein- future. andLDL cholesterol levels, largely related uria. Vascular endothelial growth factor to an acquired LDL receptor deficiency, has been implicated in human throm- which limits the removal of cholesterol- botic microangiopathy.13 The added di- EDEMA rich LDL particles from the circulation.19 mension of podocyte-secreted proteins is This reduction in uptake of extracellu- their ability to reach out to binding part- The onset of edema in nephrotic syn- lar cholesterol stimulates cholesterol ners on the surface of glomerular endo- drome occupies a clinical spectrum that biosynthesis by upregulating hepatic thelial cells and potentially participate in varies from subacute to acute onset in 3-hydroxy-3-methyl glutaryl-CoA reduc- feedback loops within the glomerulus.14 many patients with FSGS or membranous tase expression and activity in the ne- In addition to podocyte-secreted pro- nephropathy, explosive onset (often over- phrotic liver. Increased hepatic activity teins, high plasma levels of the soluble night) in MCD, and complete absence in of Acyl-CoA cholesterol acyltransferase- urokinase receptor are being investigated many patientswithHIV-related collapsing 2, an enzyme responsible for esterifica- for their role in the pathogenesis of glomerulopathy. From a pathophysiology tion of cholesterol, is also noted. Presence FSGS.15 standpoint, edemarequires a combination of normal LDL receptor mRNA expres- A new dimension recently added to of hypoalbuminemia, renal salt retention, sion in the nephrotic liver suggests a this field is the systemic response to and increased peripheral capillary perme- post-transcriptional etiology. A recent proteinuria when it reaches nephrotic ability,becausetherearenumerousclinical study in experimental animals suggests range. A circulating sialylated form of situations involving a single component that increased hepatic degradation of Angptl4 secreted predominantly from that are not associated with edema. The the LDL receptor by proprotein convertase adipose tissue, skeletal muscle, and heart variability of edema in different clinical subtilisin/kexin type 9 and inducible de- reduces proteinuria, at least in part, by situations may be directly related to differ- grader of the LDL receptor may be in- 20 binding to glomerular endothelial avb5 ences between these pathogenic compo- volved. Also, urinary loss of plasma pro- integrin.12 Thematically, it opens up a new nents. The best studied aspect and indeed, teins like lecithin–cholesterol acyltransferase area of investigation to study how other the primary target of diuretic therapy is may also contribute to hypercholesterol- organs reduce established proteinuria by renal tubular salt retention.16 In order of emia. However, the precise sequence of 2394 Journal of the American Society of Nephrology J Am Soc Nephrol 25: 2393–2398, 2014 www.jasn.org BRIEF REVIEW events and the molecular relationship of resulting in the accumulation of albu- MOLECULAR LINKS BETWEEN these changes with proteinuria remain min with higher FFA content.12,22,23 PROTEINURIA AND OTHER unknown. This loss, along with the development COMPONENTS OF NEPHROTIC of hypoalbuminemia, results in a high SYNDROME plasma FFA-to-albumin ratio, which in HYPERTRIGLYCERIDEMIA turn, drives FFA uptake in skeletal mus- There are large gaps of knowledge in our cle, heart, and adipose
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