The murine nephrin gene is specifically expressed in kidney, brain and pancreas: inactivation of the gene leads to massive proteinuria and neonatal death

Putaala, Heli; Soininen, Raija; Kilpeläinen, Pekka; Wartiovaara, Jorma; Tryggvason, Karl

doi:10.1093/hmg/10.1.1

Cited by 457 publications

(370 citation statements)

References 26 publications

Supporting

Mentioning

346

Contrasting

Unclassified

Order By: Relevance

“…Nephrin (encoded by the NPHS1 gene) was identified as the cause of disease in congenital NS of the Finnish type [60]. Nephrin-KO mouse model confirmed the essential role of nephrin in SD structure and function [61,62]. NPHS1-KO or inducible mice showed podocyte effacement with proteinuria and early postnatal death, making it unsuitable for animal model of FSGS [63] (Table 2; Fig.…”

Section: Nphs2 (Podocin) Modelmentioning

confidence: 94%

Recent advances of animal model of focal segmental glomerulosclerosis

Yang

Dettmar

Kronbichler³

et al. 2018

Clin Exp Nephrol

View full text Add to dashboard Cite

In the last decade, great advances have been made in understanding the genetic basis for focal segmental glomerulosclerosis (FSGS). Animal models using specific gene disruption of the slit diaphragm and cytoskeleton of the foot process mirror the etiology of the human disease. Many animal models have been developed to understand the complex pathophysiology of FSGS. Therefore, we need to know the usefulness and exact methodology of creating animal models. Here, we review classic animal models and newly developed genetic animal models. Classic animal models of FSGS involve direct podocyte injury and indirect podocyte injury due to adaptive responses. However, the phenotype depends on the animal background. Renal ablation and direct podocyte toxin (PAN, adriamycin) models are leading animal models for FSGS, which have some limitations depending on mice background. A second group of animal models were developed using combinations of genetic mutation and toxin, such as NEP25, diphtheria toxin, and Thy1.1 models, which specifically injure podocytes. A third group of animal models involves genetic engineering techniques targeting podocyte expression molecules, such as podocin, CD2-associated protein, and TRPC6 channels. More detailed information about podocytopathy and FSGS can be expected in the coming decade. Different animal models should be used to study FSGS depending on the specific aim and sometimes should be used in combination.

show abstract

Section: Nphs2 (Podocin) Modelmentioning

confidence: 94%

Recent advances of animal model of focal segmental glomerulosclerosis

Yang

Dettmar

Kronbichler³

et al. 2018

Clin Exp Nephrol

View full text Add to dashboard Cite

show abstract

“…Mutations in the genes encoding nephrin and podocin were the first to be identified causing inherited isolated nephrotic syndrome (NS) [26, 27], representing the major genetic cause of congenital and infantile NS, respectively. The indispensable role of nephrin ( NPHS1 ) at the slit diaphragm was shown further by the development of NPHS1 -null mice, which displayed massive proteinuria and died within 24 h of birth [28]. Ten different podocin ( NPHS2 ) mutations, comprising nonsense, frameshift and missense mutations, segregate with autosomal-recessive steroid resistant NS [27].…”

Section: The Podocyte’s Strength and Weakness: Its Actin Cytoskeletonmentioning

confidence: 99%

Podocyte Mitosis – A Catastrophe

Lasagni

Lazzeri²,

Shankland

et al. 2012

CMM

View full text Add to dashboard Cite

Podocyte loss plays a key role in the progression of glomerular disorders towards glomerulosclerosis and chronic kidney disease. Podocytes form unique cytoplasmic extensions, foot processes, which attach to the outer surface of the glomerular basement membrane and interdigitate with neighboring podocytes to form the slit diaphragm. Maintaining these sophisticated structural elements requires an intricate actin cytoskeleton. Genetic, mechanic, and immunologic or toxic forms of podocyte injury can cause podocyte loss, which causes glomerular filtration barrier dysfunction, leading to proteinuria. Cell migration and cell division are two processes that require a rearrangement of the actin cytoskeleton; this rearrangement would disrupt the podocyte foot processes, therefore, podocytes have a limited capacity to divide or migrate. Indeed, all cells need to rearrange their actin cytoskeleton to assemble a correct mitotic spindle and to complete mitosis. Podocytes, even when being forced to bypass cell cycle checkpoints to initiate DNA synthesis and chromosome segregation, cannot complete cytokinesis efficiently and thus usually generate aneuploid podocytes. Such aneuploid podocytes rapidly detach and die, a process referred to as mitotic catastrophe. Thus, detached or dead podocytes cannot be adequately replaced by the proliferation of adjacent podocytes. However, even glomerular disorders with severe podocyte injury can undergo regression and remission, suggesting alternative mechanisms to compensate for podocyte loss, such as podocyte hypertrophy or podocyte regeneration from resident renal progenitor cells. Together, mitosis of the terminally differentiated podocyte rather accelerates podocyte loss and therefore glomerulosclerosis. Finding ways to enhance podocyte regeneration from other sources remains a challenge goal to improve the treatment of chronic kidney disease in the future.

show abstract

“…Mutations in the human nephrin gene result in absence of the slit diaphragm, massive proteinuria, and a lethal disorder termed congenital nephrotic syndrome of the Finnish type (CNF) (1). A similar perinatally lethal phenotype has been described in nephrin-deficient mice (2).…”

mentioning

confidence: 90%

“…In addition to the kidney, nephrin expression has been observed in the central nervous system, developing spinal cord, cerebellum, mesencephalon, and olfactory bulb (2,11). The presence of nephrin in brain and spinal cord generated a lot of questions regarding its extrarenal functions.…”

mentioning

confidence: 99%

Alternatively Used Promoters and Distinct Elements Direct Tissue-Specific Expression of Nephrin

Beltcheva¹,

Kontusaari

Fetissov

et al. 2003

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Abstract. Nephrin, an essential component of the glomerular ultrafilter, the slit diaphragm, has also been found to be expressed in the central nervous system and pancreas. This study examined the regulation of the nephrin gene by analyzing the expression of different length nephrin promoter-lacZ reporter constructs in transgenic mice. An upstream segment between Ϫ4 kb and Ϫ4 bp was shown to be sufficient for driving expression in all three tissues. Surprisingly, a 5.7-kb construct lacking the transcription initiation site and the immediate upstream region of the gene could drive expression in the central nervous system. This led to the identification of a novel, alternatively used exon 1B located 1871 bp upstream of the ATG codon of the previously known first exon, now termed exon 1A. The existence and functionality of exon 1B was verified in nephrin knockout mice in which exon 1A is deleted. Deletion of exon 1B and its immediate surrounding sequence, introduced in the 4-kb promoter-lacZ reporter construct, abolished the expression of the transgene in pancreas and spinal cord but not in kidney and brain in transgenic mice. Analysis of five promoter-reporter gene constructs showed that regulatory elements driving expression encoded by exon 1A in kidney and brain are localized in the region between Ϫ4 kb and 2.1 kb.

show abstract

The murine nephrin gene is specifically expressed in kidney, brain and pancreas: inactivation of the gene leads to massive proteinuria and neonatal death

Cited by 457 publications

References 26 publications

Recent advances of animal model of focal segmental glomerulosclerosis

Recent advances of animal model of focal segmental glomerulosclerosis

Podocyte Mitosis – A Catastrophe

Alternatively Used Promoters and Distinct Elements Direct Tissue-Specific Expression of Nephrin

Contact Info

Product

Resources

About