The glomerular endothelial cell coat is essential for glomerular filtration

Fridén, Vincent; Oveland, Eystein; Tenstad, Olav; Ebefors, Kerstin; Nyström, Jenny; Nilsson, Ulf; Haraldsson, Börje

doi:10.1038/ki.2011.58

Cited by 113 publications

(81 citation statements)

References 40 publications

(51 reference statements)

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“…[26][27][28]49 Jeansson et al recently reported an 80% reduction in glomerular ESL depth, coupled with a 3.5-fold increase in Q albumin , shortly after induction of adrimaycin nephropathy in mice. 35 These changes are larger than in our study, which is in keeping with our finding that greater loss of glomerular ESL results in a larger increase in Q albumin .…”

Section: Discussionmentioning

confidence: 99%

Loss of the Endothelial Glycocalyx Links Albuminuria and Vascular Dysfunction

Salmon

Ferguson

Burford

et al. 2012

Journal of the American Society of Nephrology

219

202

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Patients with albuminuria and CKD frequently have vascular dysfunction but the underlying mechanisms remain unclear. Because the endothelial surface layer, a meshwork of surface-bound and loosely adherent glycosaminoglycans and proteoglycans, modulates vascular function, its loss could contribute to both renal and systemic vascular dysfunction in proteinuric CKD. Using Munich-Wistar-Fromter (MWF) rats as a model of spontaneous albuminuric CKD, multiphoton fluorescence imaging and single-vessel physiology measurements revealed that old MWF rats exhibited widespread loss of the endothelial surface layer in parallel with defects in microvascular permeability to both water and albumin, in both continuous mesenteric microvessels and fenestrated glomerular microvessels. In contrast to young MWF rats, enzymatic disruption of the endothelial surface layer in old MWF rats resulted in neither additional loss of the layer nor additional changes in permeability. Intravenous injection of wheat germ agglutinin lectin and its adsorption onto the endothelial surface layer significantly improved glomerular albumin permeability. Taken together, these results suggest that widespread loss of the endothelial surface layer links albuminuric kidney disease with systemic vascular dysfunction, providing a potential therapeutic target for proteinuric kidney disease.

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Section: Discussionmentioning

confidence: 99%

Loss of the Endothelial Glycocalyx Links Albuminuria and Vascular Dysfunction

Salmon

Ferguson

Burford

et al. 2012

Journal of the American Society of Nephrology

219

202

View full text Add to dashboard Cite

show abstract

“…39 The endothelial glycocalyx also plays a critical role in the function of the filtration barrier. 40,41 We visualized the glycocalyx using wheat germ agglutinin 40,42 but did not observe any changes in the three groups of animals studied. This contrasts with the suggested role of Angpt1 in increasing glycocalyx thickness observed in isolated glomeruli of normal healthy animals.…”

Section: Discussionmentioning

confidence: 99%

Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease

Dessapt-Baradez

Woolf

White

et al. 2014

Journal of the American Society of Nephrology

104

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Vascular growth factors play an important role in maintaining the structure and integrity of the glomerular filtration barrier. In healthy adult glomeruli, the proendothelial survival factors vascular endothelial growth factor-A (VEGF-A) and angiopoietin-1 are constitutively expressed in glomerular podocyte epithelia. We demonstrate that this milieu of vascular growth factors is altered in streptozotocin-induced type 1 diabetic mice, with decreased angiopoietin-1 levels, VEGF-A upregulation, decreased soluble VEGF receptor-1 (VEGFR1), and increased VEGFR2 phosphorylation. This was accompanied by marked albuminuria, nephromegaly, hyperfiltration, glomerular ultrastructural alterations, and aberrant angiogenesis. We subsequently hypothesized that restoration of angiopoietin-1 expression within glomeruli might ameliorate manifestations of early diabetic glomerulopathy. Podocyte-specific inducible repletion of angiopoietin-1 in diabetic mice caused a 70% reduction of albuminuria and prevented diabetes-induced glomerular endothelial cell proliferation; hyperfiltration and renal morphology were unchanged. Furthermore, angiopoietin-1 repletion in diabetic mice increased Tie-2 phosphorylation, elevated soluble VEGFR1, and was paralleled by a decrease in VEGFR2 phosphorylation and increased endothelial nitric oxide synthase Ser 1177 phosphorylation. Diabetes-induced nephrin phosphorylation was also reduced in mice with angiopoietin-1 repletion. In conclusion, targeted angiopoietin-1 therapy shows promise as a renoprotective tool in the early stages of diabetic kidney disease.

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“…Removing this layer experimentally in rat kidneys resulted in proteinuria. Identification of proteins in this glycocalyx by mass spectrometry (MS) analysis showed that orosomucoid and lumican were two of the components (Friden et al 2011). If there is a decrease in the glycocalyx in the glomerular capillaries, this may affect filtration properties and possibly contribute to increased leakage of serum proteins.…”

Section: Glycocalyx and Dnmentioning

confidence: 99%

Diabetic Nephropathy and Extracellular Matrix

Kolset

Reinholt

Jenssen

2012

J Histochem Cytochem.

244

185

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A key element in diabetic nephropathy (DN) is changes in the extracellular matrix (ECM) of several of the components in the kidney. From a clinical perspective, the changes seen in the ECM are important both in diagnostics and for prognostic and therapeutic purposes. In the current review, we present some of the central clinical issues related to DN, as well as the most relevant changes to the ECM from a diagnostic point of view, and also discuss some of the changes observed in one of the important ECM components, the proteoglycans (PGs). Our aim is not to cover all relevant research in this rather wide field, ranging from clinical trials to studies on microRNA and other important regulators of kidney function, but to focus particularly on some key issues related to PG changes in DN. Clinical Perspectives on DNAccording to estimates from the International Diabetes Federation, the worldwide prevalence of diabetes is estimated to increase from 285 million persons in 2010 to 439 millions in 2030, a relative increase of 50% (Shaw et al. 2010). Among patients with type 1 diabetes, the incidence of DN has apparently decreased from 30-35% in the cohorts who developed diabetes 40 to 50 years ago to 10-15% in recent cohorts (Bojestig et al. 1994;Hovind et al. 2003). However, due to the increase in type 2 diabetes, the absolute prevalence of DN has increased over the past two decades. In 2009, DN was reported to be the cause of 44% of all cases of end-stage renal disease (ESRD) in the United States (www.usrds.org), with an incidence of 155 diabetic patients developing ESRD per million each year. This fact was earlier announced as a "medical catastrophe of world-wide dimensions" (Ritz et al. 465073J HCXXX10.1369/0022155412465073Kolset et al.Extracellular Matrix and Diabetic Nephropathy 2012© The Author(s) 2010 Reprints and permission: sagepub.com/journalsPermissions. SummaryDiabetic nephropathy (DN) is a serious complication in diabetes. Major typical morphological changes are the result of changes in the extracellular matrix (ECM). Thus, basement membranes are thickened and the glomerular mesangial matrix and the tubulointerstitial space are expanded, due to increased amounts of ECM. One important ECM component, the proteoglycans (PGs), shows a more complex pattern of changes in DN. PGs in basement membranes are decreased but increased in the mesangium and the tubulointerstitial space. The amounts and structures of heparan sulfate chains are changed, and such changes affect levels of growth factors regulating cell proliferation and ECM synthesis, with cell attachment affecting endothelial cells and podocytes. Enzymes modulating heparan sulfate structures, such as heparanase and sulfatases, are implicated in DN. Other enzyme classes also modulate ECM proteins and PGs, such as matrix metalloproteinases (MMPs) and serine proteases, such as plasminogen activator, as well as their corresponding inhibitors. The levels of these enzymes and inhibitors are changed in plasma and in the kidneys in DN. Several growth factors, signali...

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The glomerular endothelial cell coat is essential for glomerular filtration

Cited by 113 publications

References 40 publications

Loss of the Endothelial Glycocalyx Links Albuminuria and Vascular Dysfunction

Loss of the Endothelial Glycocalyx Links Albuminuria and Vascular Dysfunction

Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease

Diabetic Nephropathy and Extracellular Matrix

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