Glomerular expression of nephrin is decreased in acquired human nephrotic syndrome

Furness, Peter; Hall, Leon L.; Shaw, Jacqui; Pringle, James H.

doi:10.1093/ndt/14.5.1234

Cited by 121 publications

(95 citation statements)

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“…Second, active metabolites including ATRA bind to retinoid receptors that are constitutively expressed in the podocytes and then transcribe their target genes. Similar mechanisms might work in human diseases because the expression of nephrin also decreases in human acquired nephrotic syndrome (45)(46)(47). In addition, ATRA might play a direct role to organize the structural components for the slit diaphragm.…”

Section: Discussionmentioning

confidence: 88%

Retinoids Regulate the Repairing Process of the Podocytes in Puromycin Aminonucleoside-induced Nephrotic Rats

Suzuki¹,

Ito²,

Imai³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. The foot processes forming the slit diaphragm are disrupted in diseases associated with proteinuria. Although they are often repairable, regulators for the repairing process remain unknown. By extrapolating from the fact that vitamin A is essential for the nephrogenesis, this study examined whether or not injured podocytes in the middle of the repairing process require retinaldehyde dehydrogenase type 2 (RALDH2), one of the key enzymes to produce all-trans-retinoic acid (ATRA). RALDH2 was dramatically upregulated in podocytes of puromycin aminonucleoside-induced nephrosis (PAN nephrosis) rats. On day 5 of PAN nephrosis, RALDH2 showed the remarkable induction, whereas glomerular expression levels of nephrin and midkine, one of the ATRA target genes, were downregulated. Daily administration of ATRA ameliorated proteinuria, which was accompanied by the improvement in the effacement of the foot processes and by the induction of nephrin and midkine. In contrast, recovery from PAN nephrosis was delayed in rats fed with a vitamin A-deficient diet. Consistently, the promoter region of human nephrin gene (NPHS1) contained three putative retinoic acid response elements (RARE) and showed the enhancer activity in response to ATRA in a dose-dependent manner. This transcriptional activation was regulated through the receptors for retinoids because BMS-189453, an antagonist to the retinoid receptors, counteracted it in a dose-dependent manner. In conclusion, active metabolites of vitamin A, especially ATRA produced by RALDH2 play relevant roles during the repairing process of injured podocytes. The results obtained from PAN nephrosis rats might be applicable to human renal diseases.

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Section: Discussionmentioning

confidence: 88%

Retinoids Regulate the Repairing Process of the Podocytes in Puromycin Aminonucleoside-induced Nephrotic Rats

Suzuki¹,

Ito²,

Imai³

et al. 2003

Journal of the American Society of Nephrology

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“…Although the precise MCD pathogenesis remains unknown, immunologic perturbations, especially in T cells (26), and subsequent injury to glomerular podocytes (27), including reduced expression of nephrin (28)(29)(30), lead to massive proteinuria in MCD. In addition to its immunomodulatory effect, corticosteroid directly affects the gene expression of podocytes (31).…”

Section: Discussionmentioning

confidence: 99%

Comparison of Methylprednisolone Plus Prednisolone with Prednisolone Alone as Initial Treatment in Adult-Onset Minimal Change Disease

Shinzawa¹,

Yamamoto²,

Nagasawa³

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives Previous studies suggested that intravenous methylprednisolone possibly accelerates remission of proteinuria in adult-onset minimal change disease; its impact on relapse of proteinuria is unknown.Design, setting, participants, & measurements This multicenter retrospective cohort study included 125 adultonset minimal change disease patients diagnosed by kidney biopsy between 2000 and 2009 and treated initially with corticosteroid in five nephrology centers in Japan participating in the Study of Outcomes and Practice Patterns of Minimal Change Disease. Times to first remission and first relapse of proteinuria after initiating the first immunosuppressive therapy were compared between 65 patients with initial use of intravenous methylprednisolone followed by prednisolone and 60 patients with initial use of prednisolone alone using multivariate Cox proportional hazards models. After calculating the probability of receiving methylprednisolone and prednisolone using a logistic regression model (propensity score), the results were ascertained using propensity score-matched and -stratified models.Results During the median 3.6 years of observation (interquartile range=2.0-6.9), all 65 patients in the methylprednisolone and prednisolone group achieved remission within 11 (8-20) days of the corticosteroid initiation, whereas in the prednisolone group, 58 of 60 patients (96.7%) achieved remission within 19 (12-37) days (P,0.001). After achieving first remission, 32 (49.2%) patients in the methylprednisolone and prednisolone group and 43 (74.1%) patients in the prednisolone group developed at least one relapse. Multivariate Cox proportional hazards models revealed that methylprednisolone and prednisolone use was significantly associated with early remission (multivariate-adjusted hazard ratio, 1.56; 95% confidence interval, 1.06 to 2.30) and lower incidence of relapse (0.50; 95% confidence interval, 0.29 to 0.85) compared with prednisolone use alone. These results were ascertained in propensity score-based models. No significant difference was observed in incidence of adverse events, including infection, aseptic osteonecrosis, cataract, diabetes, and gastrointestinal bleeding.Conclusions Initial use of methylprednisolone was associated with earlier remission and lower incidence of relapse in adult-onset minimal change disease patients. Efficacy of methylprednisolone should be evaluated in randomized controlled trials.

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“…The importance of this molecule in maintaining the glomerular barrier to protein is illustrated by the fact that humans with mutations in the NPHS1 gene and NPHS1-null mice are nephrotic and fail to develop normal podocyte foot processes (19,34). Many recent studies have associated reduced nephrin mRNA or protein expression with the onset of proteinuria in a number of nephropathies including diabetic nephropathy (35,36), minimal change disease (37), passive Heymann nephritis (38 -40), and membranous proliferative glomerulonephritis (37). Our results showing a 70% reduction in nephrin mRNA in proteinuric ACTN4-mutant mice are consistent with the observed foot process fusion and are the first to demonstrate such a correlation in the context of FSGS.…”

Section: Discussionmentioning

confidence: 99%

Focal and Segmental Glomerulosclerosis in Mice with Podocyte-Specific Expression of Mutant α-Actinin-4

Michaud

Lemieux²,

Dubé

et al. 2003

Journal of the American Society of Nephrology

143

124

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Abstract. Mutations in the gene encoding ␣-actinin-4 (ACTN4), an actin crosslinking protein, are associated with a form of autosomal dominant focal segmental glomerulosclerosis (FSGS). To better study its progression, a transgenic mouse model was developed by expressing murine ␣-actinin-4 containing a mutation analogous to that affecting a human FSGS family in a podocyte-specific manner using the murine nephrin promoter. Consistent with human ACTN4-associated FSGS, which shows incomplete penetrance, a proportion of the transgenic mice exhibited significant albuminuria (8 of 18), while the overall average systolic BP was elevated in both proteinuric and non-proteinuric ACTN4-mutant mice. Immunofluorescence confirmed podocyte-specific expression of mutant ␣-actinin-4, and real-time RT-PCR revealed that HA-ACTN4 mRNA levels were higher in proteinuric versus non-proteinuric ACTN4-mutant mice. Only proteinuric mice exhibited histologic features consistent with human ACTN4-associated FSGS, including segmental sclerosis and tuft adhesion of some glomeruli, tubular dilatation, mesangial matrix expansion, as well as regions of podocyte vacuolization and foot process fusion. Consistent with such podocyte damage, proteinuric ACTN4-mutant kidneys exhibited significantly reduced mRNA and protein levels of the slit diaphragm component, nephrin. This newly developed mouse model of human ACTN4-associated FSGS suggests a cause-and-effect relationship between actin cytoskeleton dysregulation by mutant ␣-actinin-4 and the deterioration of the nephrin-supported slit diaphragm complex.

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Glomerular expression of nephrin is decreased in acquired human nephrotic syndrome

Abstract: Abnormalities of nephrin expression appear to be associated with acquired as well as congenital causes of human nephrotic syndrome.

Cited by 121 publications

References 1 publication

Retinoids Regulate the Repairing Process of the Podocytes in Puromycin Aminonucleoside-induced Nephrotic Rats

Retinoids Regulate the Repairing Process of the Podocytes in Puromycin Aminonucleoside-induced Nephrotic Rats

Comparison of Methylprednisolone Plus Prednisolone with Prednisolone Alone as Initial Treatment in Adult-Onset Minimal Change Disease

Focal and Segmental Glomerulosclerosis in Mice with Podocyte-Specific Expression of Mutant α-Actinin-4

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