NEPHRIN

Official Full Name

NPHS1 adhesion molecule, nephrin

Organism

Homo sapiens

GeneID

4868

Background

This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes.[provided by RefSeq, Oct 2009]

Synonyms

NPHS1; CNF; NPHN; nephrin;

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Detailed Information

Nephrin, a transmembrane protein on the glomerular podocyte membrane, is an important structural molecule in the podocyte fissure membrane. Recently, it has been found that the tyrosine residue in the inner segment of Nephrin molecule is activated by the tyrosine kinase fyn (a member of the Src kinase family) to activate downstream signaling molecules to form a signal transduction pathway specific to podocytes, such as nephrin-podocin-MAPK-AP-1, nephrin-CD2AP-PI3K-Akt/PKB, nephrin-Nck-Rac/CDC42. These signaling pathways are involved in the regulation of many important physiological and pathological processes such as podocyte embryogenesis, cell survival and cytoskeletal reorganization. Similarly, the expression of nephrin protein and mRNA is also regulated by many factors.

Distribution of Nephrin

The glomerular podocyte fissure diaphragm (GPSD) is the key structure to maintain the integrity of the glomerular filtration barrier structure. In 1998, a new human gene NPHS1 was cloned in the process of studying Finnish congenital nephrotic syndrome (CNF). The in-situ hybridization technique was used to determine that its expression product was specifically localized to GPSD, so it was named Nephrin.

Nephrin belongs to the immunoglobulin superfamily molecule and is a transmembrane protein. Human Nephrin is 1241 amino acid residues long, including intracellular domain, transmembrane domain and extracellular domain. Nephrin interacts with other cleavage protein factors podocin, CD2 associated protein (CD2AP), and actinin-4 to form a major component of the glomerular filtration barrier, which plays a key role in highly specific podocyte function. In addition, the Nephrin polyprotein complex also includes cell junction-associated proteins IQGAP1, MAGI-2, CASK, spectrin, etc.

Figure 1. The proposed schematic model illustrating the molecular basis of Nephrin/MAGI1 interaction in slit diaphragm assembly and signaling. (Zhuangfeng Weng, et al. 2018)

Western blotting was used to detect human heart, brain, lung, liver, muscle, kidney, pancreas and placental tissues, and it was found that only fetal and adult kidney tissues had nephrin mRNA expression. The in-situ hybridization method was used to detect the fetal kidney tissue. It was found that only the glomerulus had the expression of Nephrin mRNA, and its distribution was similar to that of the visceral epithelial cells. Immunofluorescence electron microscopy was performed using the recombinantly expressed Nephrin N-terminal fragment as an antigen. It was confirmed that Nephrin was only distributed in the fissure membrane between the splanchnic epithelial cell foot processes, which proved that Nephrin is a structural component of the fissure membrane.

Nephrin and Kidney Disease

The clinical features of chronic nephritic syndrome (CNS) are a large number of proteinuria in the fetus, an autosomal recessive kidney disease characterized by a placental weight of more than 25% of body weight and obvious edema at birth. CNS is high in Finland and is called the Finnish CNS (CNF). The incidence rate in newborns is 1/8200. The disease progresses progressively and usually dies within 2 years of age. The only treatment is kidney transplantation. However, due to the presence of anti-Nephrin antibodies, kidney transplants tend to recur after treatment. Most of the genetic mutations in CNF have been identified, which provides a specific means for prenatal diagnosis of CNF. The genetic variation of CNF was dominated by two mutations of NPHS1, Finmajor and Finminor, accounting for 97%.

The pathological feature of membranous nephropathy (MN) is the diffuse immune complex deposition of the glomerular basement membrane (GBM) with diffuse thickening of the basement membrane. Studies have shown that patients with membranous nephropathy also have loss of podocyte barrier function and a significant decrease in the expression of Nephrin. After the podocyte cytoskeleton-actin damage, Nephrin is re-modified and exfoliated outside the cell, and α-Nephrin fragments can be detected in the urine. In the study of graft-anti-host immune rejection, cell transplantation was performed between two strains of mice, antibody against Nephrin was detected by antibody sandwich method and Nephrin and IgG immunoprecipitate were co-existed in GBM by laser confocal microscopy.

References:

Zhuangfeng Weng, Yuan Shang, Zeyang Ji, & Jinwei Zhu.. (2018) Structural basis of highly specific interaction between Nephrin and MAGI1 in slit diaphragm assembly and signaling. The 12th national congress of the Chinese society of biochemistry and molecular biology and the 2018 national academic conference.
Antiyan, E. M. , Nindya, K. I. , Masashi, A. , & Katsuhiko, A. . (2018). Magi-2 and scaffold proteins in glomerulopathy. American Journal of Physiology-Renal Physiology, ajprenal.00292.2018-.
Martin, C. E. , & Nina, J. . (2018). Nephrin signaling in the podocyte: an updated view of signal regulation at the slit diaphragm and beyond. Frontiers in Endocrinology, 9, 302-.

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