Hereditary Proteinuria Syndromes and Mechanisms of Proteinuria

Tryggvason, Karl; Patrakka, Jaakko; Wartiovaara, Jorma

doi:10.1056/nejmra052131

Cited by 490 publications

(467 citation statements)

References 98 publications

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“…Their involvement in the development of albuminuria and glomerulosclerosis in DN is increasingly accepted. 44,79 During diabetes, podocytes are exposed in vivo to high glucose levels and stretch forces, the latter because of glomerular hypertrophy and hyperfiltration. When these conditions are modeled in vitro in mouse podocytes, the RAAS becomes activated.…”

Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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“…The structural and functional alterations to the filtration barrier of kidney observed during nephrotic syndromes or other glomerular disorders are the primary causes of proteinuria (1)(2)(3). This filtration barrier is primarily composed of three major cellular layers as follows: fenestrated endothelium, glomerular basement membrane, and podocytes (2,3).…”

mentioning

confidence: 99%

Slit Diaphragm Protein Neph1 and Its Signaling

Arif

Rathore

Kumari

et al. 2014

Journal of Biological Chemistry

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Background: Neph1 is a podocyte protein that is critical for maintaining renal function. Results: Inhibiting Neph1 signaling preserves podocyte structure and function in response to glomerular injury-inducing agents. Conclusion: Maintaining a robust expression of Neph1 at the podocyte cell membrane protects podocytes from renal injury. Significance: This is the first report demonstrating that Neph1 signaling is a therapeutic target for preventing podocyte damage.

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“…ns = non significant, *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.001. Proteinuria is considered to be a hallmark of glomerular pathology [15].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Glypican-1 and 5 isoforms causes proteinuria and glomerular injury in zebrafish (Danio rerio)

Stahl¹,

Hegermann²,

Njau³

et al. 2017

Nephrol Renal Dis

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Components of the glycocalyx are being intensively studied for their involvement in a vast array of glomerular diseases. Among the most abundant proteoglycans in the glomerular cell glycocalyx are the heparan sulfate proteoglycans Glypican-1 and 5, expressed predominantly in glomerular endothelial and epithelial cells, respectively.We used a previously characterized zebrafish model to define the role of all different in zebrafish existing isoforms of Glypican-1 (a and b) and 5 (a,b and c) in vascular and renal pathology and tested the hypothesis that Glypican expression is important for the integrity of the glomerular barrier. Glypican morpholino knockdown in l-fabp:DBP-eGFP fish showed edematous phenotypes and a significant reduction of eye fluorescence for Glypican-1a, 5a und 5c, but not for Glypican1b and 5b isoforms. This indicates a significant loss of plasma proteins following knockdown of Glypican-1a, 5a and 5c in contrast to a conserved filtration barrier following knockdown of Glypican-1b and 5b isoforms. Knockdown of all different examined Glypican isoforms did not interfere with early nephron development as shown in the WT1b fish strain. Using electron microscopy, we could demonstrate that Glypican-1a knockdown leads to a predominantly endothelial cell injury with preservation of podocyte foot processes, while knockdown of Glypicans-5a and 5c shows focal podocyte effacement with conserved endothelial structures. Ultrastructural analysis of glomeruli following knockdown of Glypicans-1b and 5b reveals normal glomerular structure.In this brief study we demonstrate in an in-vivo model that the Glypican proteoglycan family is critical in vascular and glomerular integrity. Our observations suggest a role for Glypican-1a in endothelial cell and Glypican-5a and 5b in podocyte cell injury leading to subsequent loss of glomerular filtration barrier function and proteinuria.

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Hereditary Proteinuria Syndromes and Mechanisms of Proteinuria

Cited by 490 publications

References 98 publications

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Slit Diaphragm Protein Neph1 and Its Signaling

Knockdown of Glypican-1 and 5 isoforms causes proteinuria and glomerular injury in zebrafish (Danio rerio)

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