Expression of sialidase and dystroglycan in human glomerular diseases

Vogtländer, Nils P. J.; Vlag, Johan van der; Bakker, Marinka A.H.; Dijkman, Henry; Wevers, Ron A.; Campbell, Kevin P.; Wetzels, Jack F.M.; Berden, Jo H. M.

doi:10.1093/ndt/gfp465

Cited by 15 publications

(8 citation statements)

References 38 publications

(48 reference statements)

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“…This would also suggest that the pathomechanism underlying MCD may be different from that of FSGS. However, these studies have been debated because the findings in later studies by the same group 26 and other groups 27,28 were not consistent with the previous studies. 24,25 More recently it was found that urinary soluble CD80 (B7.1) is elevated in MCD and not in FSGS, which could be promising for both diagnosis and pathogenesis of the disease.…”

Section: Discussionmentioning

confidence: 88%

Detection of Activated Parietal Epithelial Cells on the Glomerular Tuft Distinguishes Early Focal Segmental Glomerulosclerosis from Minimal Change Disease

Smeets

Stucker

Wetzels

et al. 2014

The American Journal of Pathology

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In rodents, parietal epithelial cells (PECs) migrating onto the glomerular tuft participate in the formation of focal segmental glomerulosclerosis (FSGS) lesions. We investigated whether immunohistologic detection of PEC markers in the initial biopsies of human patients with first manifestation of idiopathic nephrotic syndrome with no immune complexes can improve the sensitivity to detect sclerotic lesions compared with standard methods. Ninety-five renal biopsies were stained for claudin-1 (PEC marker), CD44 (activated PECs), and LKIV69 (PEC matrix); 38 had been diagnosed as early primary FSGS and 57 as minimal change disease. PEC markers were detected on the tuft in 87% of the biopsies of patients diagnosed as primary FSGS. PEC markers were detected in FSGS lesions from the earliest stages of disease. In minimal change disease, no PEC activation was observed by immunohistology. However, in 25% of biopsies originally diagnosed as minimal change disease the presence of small lesions indicative of a sclerosing process were detected, which were undetectable on standard periodic acid-Schiff staining, even though only a single histologic section for each PEC marker was evaluated. Staining for LKIV69 detected lesions with the highest sensitivity. Two novel PEC markers A-kinase anchor protein 12 and annexin A3 exhibited similar sensitivity. In summary, detection of PECs on the glomerular tuft by immunostaining improves the differentiation between minimal change disease and primary FSGS and may serve to guide clinical decision making.

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Section: Discussionmentioning

confidence: 88%

Detection of Activated Parietal Epithelial Cells on the Glomerular Tuft Distinguishes Early Focal Segmental Glomerulosclerosis from Minimal Change Disease

Smeets

Stucker

Wetzels

et al. 2014

The American Journal of Pathology

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“…PNA-positive glomeruli are also observed in human glomerular disease, due to increased endogenous glomerular sialidase, and in diabetic nephropathy due to disturbed glycan turnover [41], [42]. Since galactose-containing epitopes, Galβ1-3GalNAc and Galβ1-4GlcAc, which are recognized by PNA and RCA-I, respectively, are usually highly sialylated, these lectins cannot recognize these sialylated epitopes in ht-mice.…”

Section: Discussionmentioning

confidence: 99%

“…Our mt-mice are suitable for long-term therapeutic trials and the pathological analysis of nephrotic-like syndromes. We consider the negatively charged monosaccharide Neu5Ac to be a promising therapeutic tool for some nephrotic syndromes; candidate disorders include focal and segmental glomerulonephritis [42], [47], membranous glomerulopathy [42], and other unexplained nephrotic syndromes, congenital or otherwise. However, no renal diseases caused by hyposialylation have been identified to date, and renal abnormality has not been reported in DMRV patients.…”

Section: Discussionmentioning

confidence: 99%

Glycoprotein Hyposialylation Gives Rise to a Nephrotic-Like Syndrome That Is Prevented by Sialic Acid Administration in GNE V572L Point-Mutant Mice

et al. 2012

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Mutations in the key enzyme of sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetyl-mannosamine kinase, result in distal myopathy with rimmed vacuoles (DMRV)/hereditary inclusion body myopathy (HIBM) in humans. Sialic acid is an acidic monosaccharide that modifies non-reducing terminal carbohydrate chains on glycoproteins and glycolipids, and it plays an important role in cellular adhesions and interactions. In this study, we generated mice with a V572L point mutation in the GNE kinase domain. Unexpectedly, these mutant mice had no apparent myopathies or motor dysfunctions. However, they had a short lifespan and exhibited renal impairment with massive albuminuria. Histological analysis showed enlarged glomeruli with mesangial matrix deposition, leading to glomerulosclerosis and abnormal podocyte foot process morphologies in the kidneys. Glycan analysis using several lectins revealed glomerular epithelial cell hyposialylation, particularly the hyposialylation of podocalyxin, which is one of important molecules for the glomerular filtration barrier. Administering Neu5Ac to the mutant mice from embryonic stages significantly suppressed the albuminuria and renal pathology, and partially recovered the glomerular glycoprotein sialylation. These findings suggest that the nephrotic-like syndrome observed in these mutant mice resulted from impaired glomerular filtration due to the hyposialylation of podocyte glycoproteins, including podocalyxin. Furthermore, it was possible to prevent the nephrotic-like disease in these mice by beginning Neu5Ac treatment during gestation.

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“…Giannico et al in a study of adult cohort documented no reduction in expression of beta dystroglycan in MCD, whereas alpha dystroglycan was reduced in MCD [7]. However, Vogtlander et al documented that there was no difference in the staining pattern of alpha dystroglycan in nephrotic syndrome cases [6] (Table 4). …”

Section: Discussionmentioning

confidence: 99%

Podocin and Beta Dystroglycan expression to study Podocyte-Podocyte and basement membrane matrix connections in adult protienuric states

et al. 2014

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BackgroundPodocytes can be the primary site of injury or secondarily involved in various protienuric states. Cross talk between adjacent foot processes and with basement membrane is important for slit diaphragm function. Does expression of podocyte associated proteins in kidney biopsies alter with site/type of primary injury? Genetic mutations of podocin result in steroid resistant FSGS. Can protein expression of podocin predict resistant cases to initiate further genetic evaluation?MethodsAdult patients (n-88) with protienuria- minimal change disease(MCD)-22, focal segmental glomerulosclerosis(FSGS)-21,membranous glomerulonephritis(MGN)-25 and IgA nephropathy(IgAN)-20 were selected for immunohistochemistry with podocin and beta dystroglycan . Results were graded (0 - 3+scale )and compared with control biopsies and internal control. Treatment and follow up (6 months -2 ½ years) of FSGS and MCD cases were collected.ResultsThere was intense to moderate staining of the podocytes with podocin and β dystroglycan in the glomeruli in all cases (MCD, FSGS, IgAN and MGN) except for weak staining with β dystroglycan in 3 cases of MCD. There was loss of immunostains in areas of segmental/global sclerosis. There was no significant difference in the staining pattern between the groups. In primary podocytopathies, staining pattern did not differ between steroid resistant, sensitive or dependent cases.ConclusionsImmunohistochemical expression of podocin and β dystroglycan does not differ in nephropathies which have different site of injury depending on absence (MCD and FSGS) or presence of immune deposits and their localization (MGN and IgAN). Podocin and β dystroglycan staining did not differentiate steroid sensitive and resistant cases, hence, does not give clue to initiate genetic studies. However, analysis of bigger cohort may be required.SummaryPodocin and β dystroglycan immunohistochemistry was done to analyze podocyte - podocyte and podocyte -basement membrane matrix connections in adult protienuric states. Primary podocytopathies i.e. MCD and FSGS and secondary podocytopathy due to immune complex deposition i.e. MGN (subepithelial) and IgAN (mesangial) were analyzed. There was no difference in staining patterns between primary and secondary podocytopathies or between steroid sensitive, resistant and dependent cases of FSGS and MCD.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2258608781052786

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Expression of sialidase and dystroglycan in human glomerular diseases

Abstract: Endogenous glomerular sialidase expression is increased in MG, which might represent a novel mechanism for the loss of negative charge in the glomerular capillary filter. The expression of dystroglycan cannot be used as a diagnostic tool to differentiate between glomerular diseases.

Cited by 15 publications

References 38 publications

Detection of Activated Parietal Epithelial Cells on the Glomerular Tuft Distinguishes Early Focal Segmental Glomerulosclerosis from Minimal Change Disease

Detection of Activated Parietal Epithelial Cells on the Glomerular Tuft Distinguishes Early Focal Segmental Glomerulosclerosis from Minimal Change Disease

Glycoprotein Hyposialylation Gives Rise to a Nephrotic-Like Syndrome That Is Prevented by Sialic Acid Administration in GNE V572L Point-Mutant Mice

Podocin and Beta Dystroglycan expression to study Podocyte-Podocyte and basement membrane matrix connections in adult protienuric states

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