Management of congenital nephrotic syndrome of the Finnish type

Holmberg, Christer; Antikainen, Marjatta; Rönnholm, Kai; Ala‐Houhala, Marja; Jalanko, Hannu

doi:10.1007/bf00858984

Cited by 187 publications

(171 citation statements)

References 37 publications

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“…15,19,20,23 Thus, the recent identification of the NPHS1 gene 14 responsible for this disease phenotype has suggested that this gene and the respective protein product nephrin play some key roles in the maintenance of the glomerular filtration barrier. Kestilä et al 14 showed that NPHS1 encodes a putative transmembrane protein with sequence similarity to that of cell adhesion molecules of the immunoglobulin superfamily and with expression in the kidney but not in other tissues.…”

Section: Discussionmentioning

confidence: 99%

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Cloning and Expression of the Rat Nephrin Homolog

Ahola¹,

Wang²,

Luimula³

et al. 1999

The American Journal of Pathology

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Despite of the increased availability of genetically modified mouse strains , the experimental models in the rat have provided the most widely employed and versatile models for the study of renal pathophysiology and functional genetics. The identification of the human gene mutated in the congenital nephrotic syndrome of the Finnish type (NPHS1) has recently been reported , and its protein product has been termed nephrin. Here we report the molecular cloning and characterization of rat nephrin cDNA. Rat nephrin cDNA has an open reading frame of 3705 bp , shows 82% sequence identity with human nephrin cDNA, and shows characteristic rat-specific splicing variants. The translated nucleotide sequence has 89% sequence identity at the amino acid level. The signal sequence , glycosylation , and cysteine localization patterns are nearly identical to those of human nephrin. As in the human , the rat nephrin transcript is expressed in a tissue-restricted pattern. Antipeptide antibodies raised to the intracellular nephrin-specific domain identified immunoreactivity exclusively within the rat kidney glomerulus by indirect immunofluorescence. Initial results with semiquantitative reverse transcriptase-polymerase chain reaction analysis showed a remarkable down-regulation of nephrin-specific mRNA in the puromycin nephrosis of the rat. (Am J Pathol 1999, 155:907-913)The molecular pathogenesis of diseases that result in abnormalities of glomerular filtration has remained poorly understood. Recent results indicate that podocytes play an important role in regulating the passage of macromolecules and have several structural properties suitable for allowing the rapid modulation of the permeability barrier.

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Section: Discussionmentioning

confidence: 99%

“…The current treatment of CNF with early nephrectomy and final renal transplantation appears to cure all symptoms. 15 After transplantation, no new symptoms are reported after several years of followup. The results of Kestilä et al 14 showed that NPHS1 is only expressed in the kidney glomerulus.…”

mentioning

confidence: 98%

Cloning and Expression of the Rat Nephrin Homolog

Ahola¹,

Wang²,

Luimula³

et al. 1999

The American Journal of Pathology

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“…30 Kidney transplantation within the first year can safe the life of nephrindeficient children. 31 These children are free from any symptoms in other nephrin-expressing tissues 32,33 except for an increase in muscular dystonia and mild ataxia in some cases. 34 In the present study, it is shown that induction of transgenic rat nephrin expression early during embryonic development (E11) exclusively in the podocytes rescues nephrin deficient mice from perinatal death.…”

Section: Discussionmentioning

confidence: 99%

Inducible Nephrin Transgene Expression in Podocytes Rescues Nephrin-Deficient Mice from Perinatal Death

Juhila

Lassila

Roozendaal

et al. 2010

The American Journal of Pathology

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Mutations leading to nephrin loss result in massive proteinuria both in humans and mice. Early perinatal lethality of conventional nephrin knockout mice makes it impossible to determine the role of nephrin protein in the adult kidney and in extra-renal tissues. Herein , we studied whether podocyte-specific , doxycycline-inducible , rat nephrin expression can rescue nephrin-deficient mice from perinatal lethality. Fourteen littermates out of 72 lacked endogenous nephrin and expressed transgenic rat nephrin. Six of these rescued mice survived until 6 weeks of age , whereas the nephrin-deficient pups died before the age of 5 days. The rescued mice were smaller , developed proteinuria , and showed histological abnormalities in the kidney. Despite foot process effacement , slit diaphragms were observed. Importantly , the expression and localization of several proteins associated with the signaling capacity of nephrin or the regulation of the expression of nephrin were changed in the podocytes. Indeed , all rescued mice showed impaired locomotor activity and distinct histological abnormalities in the cerebellum , and the male mice were also infertile and showed genital malformations. These observations are consistent with normal nephrin expression in the testis and cerebellum. These observations indicate that podocyte-specific expression of rat nephrin can rescue nephrin-deficient mice from perinatal death , but is not sufficient for full complementation.

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“…Therapies with agents to reduce the glomerular filtration pressure have not been successful in reducing the proteinuria. Children with CNF are currently treated with bilateral nephrectomy and dialysis, followed by renal transplantation [58,59].…”

Section: Nephrin In Congenital Nephrotic Syndrome Of Finnish Typementioning

confidence: 99%

An update: the role of Nephrin inside and outside the kidney

2015

Sci. China Life Sci.

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Nephrin is a key molecule in podocytes to maintain normal slit diaphragm structure. Nephin interacts with many other podocyte and slit diaphragm protein and also mediates important cell signaling pathways in podocytes. Loss of nephrin during the development leads to the congenital nephrotic syndrome in children. Reduction of nephrin expression is often observed in adult kidney diseases including diabetic nephropathy and HIV-associated nephropathy. The critical role of nephrin has been confirmed by different animal models with nephrin knockout and knockdown. Recent studies demonstrate that knockdown of nephrin expression in adult mice aggravates the progression of unilateral nephrectomy and Adriamycin-induced kidney disease. In addition to its critical role in maintaining normal glomerular filtration unit in the kidney, nephrin is also expressed in other organs. However, the exact role of nephrin in kidney and extra-renal organs has not been well characterized. Future studies are required to determine whether nephrin could be developed as a drug target to treat patients with kidney disease.

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Management of congenital nephrotic syndrome of the Finnish type

Cited by 187 publications

References 37 publications

Cloning and Expression of the Rat Nephrin Homolog

Cloning and Expression of the Rat Nephrin Homolog

Inducible Nephrin Transgene Expression in Podocytes Rescues Nephrin-Deficient Mice from Perinatal Death

An update: the role of Nephrin inside and outside the kidney

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