Tion, a Cys in the fibronectinlike region may kind a disulfide bond with a further nephrin molecule or with an unknown protein connecting the slit diaphragm plus the cytoskeleton. In summary, the three free of charge Cys residues participate in the formation of intermolecular disulfide bonds that enhance the integrity with the slit diaphragm. Deletion of these 3 Cys residues may possibly relax the slit diaphragm, leading to its disappearance, disrupting the filtration barrier and inducing proteinuria [25]. A gene mutation in nephrin can bring about congenital nephrotic syndrome from the Finnish kind (CNF), with clinical characteristics like massive intrauterine proteinuria, a placental weight exceeding the body weight by 25 at birth and significant edema. This syndrome is progressive, and sufferers typically die inside two years right after birth. At the initial day after intravenous injection of extracellular antinephrin monoclonal antibody (mAb)516 into rats, massive proteinuria has been shown to emerge and to peak on day 5. Studies on models of nephrotoxic serum nephritis, Heymann nephritis, and amino nucleotide nephropathy determined that the expression of nephrin in renal structures of mice was considerably decreased in the model group. In addition, the mice created enormous proteinuria [25, 26]. 5.two. Podocin and Proteinuria. Podocin is definitely an integral membrane protein that was detected even though studying steroidresistant congenital nephrotic syndrome applying targeted cloning technology. It truly is encoded by the NPHS2 gene [27]. Podocin is usually a new member with the stomatin household of lipid raftassociated proteins and consists of 383 amino acids using the molecular weight of 42 kDa along with a “hairpinlike” single membrane area. Its N and Ctermini are positioned within the cytoplasm. Podocin interacts with nephrin and CD2AP by means of its Cterminus. It plays a vital role in maintainingInternational Journal of Nephrology the structure and function of SDs as a supporting protein. Research in zebra fish discovered that at 72 and 96 h immediately after fertilization, the expression of glomerular podocin protein decreased or disappeared, major to abnormalities in slit diaphragms and stopping the formation of typical podocytic processes [27]. NPHS2 geneencoding podocin knockout mice showed proteinuria prior to birth and died within numerous days following birth; their pathological manifestation was severe mesentery sclerosis. In depth subpodocytic fusion and slit membrane disappearance might be observed through electron microscopy. NPHS2 gene mutations happen to be detected in syndromes for instance human congenital familial steroidresistant nephrotic syndrome and sporadic steroidresistant nephrotic syndrome [280], suggesting that podocin plays a crucial role in sustaining the structure of podocytic processes and the integrity of slit membranes. Podocin may very well be of wonderful significance inside the pathogenesis of proteinuria. five.three. CD2AP and Proteinuria. CD2AP is usually a transmembrane protein belonging for the immunoglobulin superfamily and is composed of 639 amino acids having a molecular weight of 80 kDa. It was initially determined that, as an intracellular ligand of T cell and organic killer cell CD2 receptors, CD2AP can stabilize connections in between T cells and antigenpresenting cells. Furthermore, CD2AP is extensively expressed in several structures of humans and mice, and it has been shown by way of immunoelectron Phenyl acetate Epigenetics microscopy that CD2AP localizes near the intracellular segment of nephrin inside the podocyte side wall. Simultaneous immunofluorescence.
