Urinary heparanase activity in patients with Type 1 and Type 2 diabetes

Rops, Angelique L.; Hoven, Mabel J. van den; Veldman, B.A.J.; Salemink, Simone; Vervoort, G.M.M.; Elving, L.D.; Aten, Jan; Wetzels, Jack F.M.; Vlag, Johan van der; Berden, Jo H. M.

doi:10.1093/ndt/gfr732

Cited by 42 publications

(40 citation statements)

References 38 publications

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“…It should be noted that different cellular origins of heparanase and CatL imply that proteolytic activation of heparanase by CatL can occur extracellularly, which is in agreement with the previously reported secreted nature of both proteins in kidney (10,49).…”

Section: C and D)supporting

confidence: 91%

“…Involvement of heparanase in diabetic nephropathy (DN) was suggested more than a decade ago, owing to elevated levels of the enzyme in the kidneys and urine of DN patients, induction of renal heparanase in murine DN models, as well as in vitro studies demonstrating the upregulation of heparanase in kidney-derived cell lines by hyperglycemic conditions and DN mediators (i.e., albumin and advanced glycation end products [AGEs]) (8)(9)(10)(11)(12).…”

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confidence: 99%

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Role of Heparanase-Driven Inflammatory Cascade in Pathogenesis of Diabetic Nephropathy

et al. 2014

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Renal involvement is a major medical concern in the diabetic population, and with the global epidemic of diabetes, diabetic nephropathy (DN) became the leading cause of end-stage renal failure in the Western world. Heparanase (the only known mammalian endoglycosidase that cleaves heparan sulfate) is essentially involved in DN pathogenesis. Nevertheless, the exact mode of heparanase action in sustaining the pathology of DN remains unclear. Here we describe a previously unrecognized combinatorial circuit of heparanase-driven molecular events promoting chronic inflammation and renal injury in individuals with DN. These events are fueled by heterotypic interactions among glomerular, tubular, and immune cell compartments, as well as diabetic milieu (DM) components. We found that under diabetic conditions latent heparanase, overexpressed by glomerular cells and posttranslationally activated by cathepsin L of tubular origin, sustains continuous activation of kidneydamaging macrophages by DM components, thus creating chronic inflammatory conditions and fostering macrophage-mediated renal injury. Elucidation of the mechanism underlying the enzyme action in diabetic kidney damage is critically important for the proper design and future implementation of heparanase-targeting therapeutic interventions (which are currently under intensive development and clinical testing) in individuals with DN and perhaps other complications of diabetes.

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Section: C and D)supporting

confidence: 91%

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confidence: 99%

Role of Heparanase-Driven Inflammatory Cascade in Pathogenesis of Diabetic Nephropathy

et al. 2014

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“…The promotion of EMT may be facilitated 10 or not 12 by a transforming growth factor β-dependent mechanism and appears to be mediated through a heparanase-stimulating process 10 known to be involved in the pathogenesis of several proteinuric nephropathies. 13,14 In contrast, low dose of everolimus, commonly used during organ transplant, failed to induce EMT in the same experimental settings. 10 Therefore, mTOR inhibitor-associated nephrotoxicity is characterized predominantly by a possible apoptotic renal epithelial cell injury 15 that affects both podocytes [7][8][9]11,[16][17][18][19] in the glomerular compartment and renal tubular epithelial cells 10,[20][21][22][23][24] in the tubulointerstitial compartment.…”

Section: Case Discussion and Review Of The Literaturementioning

confidence: 98%

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2015

Exp Clin Transplant

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Mammalian target of rapamycin inhibitors, such as rapamycin and more recently everolimus, have substituted calcineurin inhibitors in many minimization strategies. Despite their acclaimed renal safety profile, several lines of evidence are emerging on their potential nephrotoxic effect. Predisposing conditions for nephrotoxicity involve a complex interplay between several environmental and genetic factors in the donor-recipient pair. Renal injury may be enhanced by pharmacodynamic interactions when combined with other drugs such as calcineurin inhibitors or nutrients that are predominantly related to an increase in local tissue exposure. These toxic interactions may occur within adequate doses and therapeutic blood levels. This explains the occurrence of nephrotoxicity in some but not all cases. Here, we postulated that activity of a low permeability glycoprotein efflux pump related to low protein expression and/or inhibition enhanced immunosuppressive drug entry in different cells. A rise in intracellular drug concentration increases bioactivity, leading to greater immunosuppression and more immune-related, nonrenal adverse events in the recipient and increased nephrotoxicity in the kidney graft. Under specific isolated or combined environmental and/or genetic conditions in both the recipient and donor affecting the glycoprotein efflux pump and/or the mammalian target of rapamycin pathway, these renal injuries may be aggravated by heightened drug tissue concentrations despite adherence to therapeutic drug and blood levels. Mammalian target of rapamycin inhibitors may induce predominantly a dose-dependent renal epithelial cell injury affecting either the glomerular or the renal tubular epithelial cells, leading to cell death and apoptosis. Epithelial mesenchymal transitionmediated interstitial fibrosis and tubular atrophy observed with these drugs may be the result of a cumulative toxic renal tubular injury induced by the direct insult of the drug itself and/or podocytopathy-associated proteinuria. The resulting glomerular tubular damage will ultimately lead to graft failure and loss, if exposure persists.

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“…This event is sustained by the release of matrix metalloproteinases (MMPs) [24,25] and heparanase (HPSE) [26-28], an endoglycosidase that cleaves heparan sulphate chains involved in the pathogenesis of several proteinuric nephropathies [29,30] and onset of chronic allograft dysfunction [31]. …”

Section: Introductionmentioning

confidence: 99%

Everolimus-induced epithelial to mesenchymal transition in immortalized human renal proximal tubular epithelial cells: key role of heparanase

et al. 2013

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BackgroundEverolimus (EVE) is a drug widely used in several renal transplant protocols. Although characterized by a relatively low nephrotoxicity, it may induce several adverse effects including severe fibro-interstitial pneumonitis. The exact molecular/biological mechanism associated to these pro-fibrotic effects is unknown, but epithelial to mesenchymal transition (EMT) may have a central role. Additionally, heparanase, an enzyme recently associated with the progression of chronic allograft nephropathy, could contribute to activate this machinery in renal cells.MethodsSeveral biomolecular strategies (RT-PCR, immunofluorescence, zymography and migration assay) have been used to assess the capability of EVE (10, 100, 200 and 500 nM) to induce an in vitro heparanase-mediated EMT in wild-type (WT) and Heparanase (HPSE)-silenced immortalized human renal epithelial proximal tubular cells (HK-2). Additionally, microarray technology was used to find additional biological elements involved in EVE-induced EMT.ResultsBiomolecular experiments demonstrated a significant up-regulation (more than 1.5 fold increase) of several genes encoding for well known EMT markers [(alpha-smooth muscle actin (α-SMA), Vimentin (VIM), Fibronectin (FN) and matrix metalloproteinase-9 (MMP9)], enhancement of MMP9 protein level and increment of cells motility in WT HK2 cells treated with high concentrations of EVE (higher than 100 nM). Similarly, immunofluorescence analysis showed that 100 nM of EVE increased α-SMA, VIM and FN protein expression in WT HK2 cells. All these effects were absent in both HPSE- and AKT-silenced cell lines. AKT is a protein having a central role in EMT. Additionally, microarray analysis identified other 2 genes significantly up-regulated in 100 nM EVE-treated cells (p < 0.005 and FDR < 5%): transforming growth factor beta-2 (TGFβ2) and epidermal growth factor receptor (EGFR). Real-time PCR analysis validated microarray.ConclusionsOur in vitro study reveals new biological/cellular aspects of the pro-fibrotic activity of EVE and it demonstrates, for the first time, that an heparanase-mediated EMT of renal tubular cells may be activated by high doses of this drug. Additionally, our results suggest that clinicians should administer the adequate dosage of EVE in order to increase efficacy and reduce adverse effects. Finally heparanase could be a new potential therapeutic target useful to prevent/minimize drug-related systemic fibrotic adverse effects.

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Urinary heparanase activity in patients with Type 1 and Type 2 diabetes

Abstract: Urinary heparanase activity is increased in diabetic patients with proteinuria. However, whether increased heparanase activity is a cause or consequence of proteinuria requires additional research.

Cited by 42 publications

References 38 publications

Role of Heparanase-Driven Inflammatory Cascade in Pathogenesis of Diabetic Nephropathy

Role of Heparanase-Driven Inflammatory Cascade in Pathogenesis of Diabetic Nephropathy

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Everolimus-induced epithelial to mesenchymal transition in immortalized human renal proximal tubular epithelial cells: key role of heparanase

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