Contribution of Proteoglycans Towards the Integrated Functions of Renal Glomerular Capillaries

Kanwar, Yashpal S.; Danesh, Farhad R.; Chugh, Sumant S.

doi:10.2353/ajpath.2007.070356

Cited by 25 publications

(23 citation statements)

References 29 publications

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“…It is interesting to note that the biological functions of kidney HS linked to filtration are still a matter of debate (Raats et al 2000;Kanwar et al 2007;Morita et al 2008). There has so far been little focus on the possible importance of kidney CS/DS for filtration or other kidney functions.…”

Section: Discussionmentioning

confidence: 99%

“…Also, knocking out the HS polymerase system (exostosin-1, EXT1) in podocytes affected cellular morphology, but was not accompanied by albuminuria (Chen et al 2008). The complexity of this issue has been reviewed (Raats et al 2000;Kanwar et al 2007) and debated (Morita et al 2008) and concerns several factors that contribute to kidney filtration, such as nephrin slits and the glycocalyx on endothelial cells. Changes in HSPGs in the tubulointerstitial space also contribute to proteinuria (Celie et al 2008).…”

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confidence: 99%

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Reduced Sulfation of Chondroitin Sulfate but Not Heparan Sulfate in Kidneys of Diabetic db/db Mice

Reine

Grøndahl

Jenssen

et al. 2013

J Histochem Cytochem.

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Heparan sulfate proteoglycans are hypothesized to contribute to the filtration barrier in kidney glomeruli and the glycocalyx of endothelial cells. To investigate potential changes in proteoglycans in diabetic kidney, we isolated glycosaminoglycans from kidney cortex from healthy db/+ and diabetic db/db mice. Disaccharide analysis of chondroitin sulfate revealed a significant decrease in the 4-O-sulfated disaccharides (D0a4) from 65% to 40%, whereas 6-O-sulfated disaccharides (D0a6) were reduced from 11% to 6%, with a corresponding increase in unsulfated disaccharides. In contrast, no structural differences were observed in heparan sulfate. Furthermore, no difference was found in the molar amount of glycosaminoglycans, or in the ratio of hyaluronan/heparan sulfate/chondroitin sulfate. Immunohistochemical staining for the heparan sulfate proteoglycan perlecan was similar in both types of material but reduced staining of 4-O-sulfated chondroitin and dermatan was observed in kidney sections from diabetic mice. In support of this, using qRT-PCR, a 53.5% decrease in the expression level of Chst-11 (chondroitin 4-O sulfotransferase) was demonstrated in diabetic kidney. These results suggest that changes in the sulfation of chondroitin need to be addressed in future studies on proteoglycans and kidney function in diabetes.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Reduced Sulfation of Chondroitin Sulfate but Not Heparan Sulfate in Kidneys of Diabetic db/db Mice

Reine

Grøndahl

Jenssen

et al. 2013

J Histochem Cytochem.

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“…Also, using a panel of HS antibodies, no sulfation changes were detected in the glomeruli of diabetic rat renal tissue (van den Born et al 2006).The issue of the importance of HS as a filtration barrier in the kidney is debated (Kanwar et al 2007;Harvey and Miner 2008). In addition to the BM, the endothelial cell layer with the glycocalyx facing the bloodstream, other negatively charged ECM molecules than PGs, and the podocytes, with their associated slit diaphragms, all represent parts of a barrier system in the kidneys (Kanwar et al 2007;Kanwar et al 2011;Miner 2012). Early work suggested that low-dose heparin could reduce proteinuria in patients with type 1 diabetes (Myrup et al 1995).…”

Section: Proteoglycans and The Kidneymentioning

confidence: 99%

Diabetic Nephropathy and Extracellular Matrix

Kolset

Reinholt

Jenssen

2012

J Histochem Cytochem.

255

186

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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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“…7 The correct assembly of this epithelial layer is critical in the generation and maintenance of the glomerular barrier to protein ultrafiltration. [8][9][10][11] By using an optimized reaggregation system 12 we recently showed that organoids constructed in vitro using suspensions of fully dissociated mouse kidney cells were integrated into a living recipient, and grew to form vascularized glomeruli that exhibited well formed capillary structures and filtration slits. These organoids were also competent at exerting kidney specific functions in terms of blood filtration, tubular reabsorption of macromolecules and erythropoietin production.…”

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confidence: 99%

Functional Human Podocytes Generated in Organoids from Amniotic Fluid Stem Cells

Xinaris

Benedetti

Novelli

et al. 2015

JASN

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Generating kidney organoids using human stem cells could offer promising prospects for research and therapeutic purposes. However, no cell-based strategy has generated nephrons displaying an intact threedimensional epithelial filtering barrier. Here, we generated organoids using murine embryonic kidney cells, and documented that these tissues recapitulated the complex three-dimensional filtering structure of glomerular slits in vivo and accomplished selective glomerular filtration and tubular reabsorption. Exploiting this technology, we mixed human amniotic fluid stem cells with mouse embryonic kidney cells to establish three-dimensional chimeric organoids that engrafted in vivo and grew to form vascularized glomeruli and tubular structures. Human cells contributed to the formation of glomerular structures, differentiated into podocytes with slit diaphragms, and internalized exogenously infused BSA, thus attaining in vivo degrees of specialization and function unprecedented for donor stem cells. In conclusion, human amniotic fluid stem cell chimeric organoids may offer new paths for studying renal development and human podocyte disease, and for facilitating drug discovery and translational research.

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Contribution of Proteoglycans Towards the Integrated Functions of Renal Glomerular Capillaries

Cited by 25 publications

References 29 publications

Reduced Sulfation of Chondroitin Sulfate but Not Heparan Sulfate in Kidneys of Diabetic db/db Mice

Reduced Sulfation of Chondroitin Sulfate but Not Heparan Sulfate in Kidneys of Diabetic db/db Mice

Diabetic Nephropathy and Extracellular Matrix

Functional Human Podocytes Generated in Organoids from Amniotic Fluid Stem Cells

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