Nephrin Explained

Nephrin is a protein necessary for the proper functioning of the renal filtration barrier. The renal filtration barrier consists of fenestrated endothelial cells, the glomerular basement membrane, and the podocytes of epithelial cells. Nephrin is a transmembrane protein that is a structural component of the slit diaphragm.^[1] It is present on the tips of the podocytes as an intricate mesh connecting adjacent foot processes. Nephrin contributes to the strong size selectivity of the slit diaphragm,^{[2] [3]} however, the relative contribution of the slit diaphragm to exclusion of protein by the glomerulus is debated.^{[2] [4]} The extracellular interactions, both homophilic and heterophilic—between nephrin and NEPH1—are not completely understood.^[2] In addition to eight immunoglobulin G–like motifs and a fibronectin type 3 repeat, nephrin has a single transmembrane domain and a short intracellular tail.^{[2] [3]} Tyrosine phosphorylation at different sites on the intracellular tail contribute to the regulation of slit diaphragm formation during development^[3] and repair in pathology affecting podocytes.^{[2] [3]} Podocin may interact with nephrin to guide it onto lipid rafts in podocytes, requiring the integrity of an arginine residue of nephrin at position 1160.^[3]

A defect in the gene for nephrin, NPHS1, is associated with congenital nephrotic syndrome of the Finnish type and causes massive amounts of protein to be leaked into the urine, or proteinuria. Nephrin is also required for cardiovascular development.^[5]

Interactions

Nephrin has been shown to interact with:

• CASK,
• CD2AP,^[6]
• CDH3^[6] and
• CTNND1,^[6]
• FYN,^{[7] [8]}
• KIRREL,^{[9] [10]} and
• NPHS2.^[11]

See also

• Podocyte

Further reading

• Tryggvason K . Nephrin: role in normal kidney and in disease. . Adv. Nephrol. Necker Hosp. . 31 . 221–34 . 2002 . 11692461 .
• Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K . Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome. . Mol. Cell . 1 . 4 . 575–82 . 1998 . 9660941 . 10.1016/S1097-2765(00)80057-X . free .
• Lenkkeri U, Männikkö M, McCready P, Lamerdin J, Gribouval O, Niaudet PM, Antignac CK, Kashtan CE, Homberg C, Olsen A, Kestilä M, Tryggvason K . Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations. . Am. J. Hum. Genet. . 64 . 1 . 51–61 . 1999 . 9915943 . 1377702 . 10.1086/302182 .
• Ruotsalainen V, Ljungberg P, Wartiovaara J, Lenkkeri U, Kestilä M, Jalanko H, Holmberg C, Tryggvason K . Nephrin is specifically located at the slit diaphragm of glomerular podocytes. . Proc. Natl. Acad. Sci. U.S.A. . 96 . 14 . 7962–7 . 1999 . 10393930 . 22170 . 10.1073/pnas.96.14.7962 . 1999PNAS...96.7962R . free .
• Bolk S, Puffenberger EG, Hudson J, Morton DH, Chakravarti A . Elevated frequency and allelic heterogeneity of congenital nephrotic syndrome, Finnish type, in the old order Mennonites. . Am. J. Hum. Genet. . 65 . 6 . 1785–90 . 2000 . 10577936 . 1288392 . 10.1086/302687 .
• Aya K, Tanaka H, Seino Y . Novel mutation in the nephrin gene of a Japanese patient with congenital nephrotic syndrome of the Finnish type. . Kidney Int. . 57 . 2 . 401–4 . 2000 . 10652016 . 10.1046/j.1523-1755.2000.00859.x . free .
• Li C, Ruotsalainen V, Tryggvason K, Shaw AS, Miner JH . CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere. . Am. J. Physiol. Renal Physiol. . 279 . 4 . F785–92 . 2000 . 10997929 . 10.1152/ajprenal.2000.279.4.F785. 37166239 . free .
• Huber TB, Kottgen M, Schilling B, Walz G, Benzing T . Interaction with podocin facilitates nephrin signaling. . J. Biol. Chem. . 276 . 45 . 41543–6 . 2001 . 11562357 . 10.1074/jbc.C100452200 . free .
• Palmén T, Ahola H, Palgi J, Aaltonen P, Luimula P, Wang S, Jaakkola I, Knip M, Otonkoski T, Holthöfer H . Nephrin is expressed in the pancreatic beta cells. . Diabetologia . 44 . 10 . 1274–80 . 2002 . 11692176 . 10.1007/s001250100641 . free .
• Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W, Shaw AS, Holzman LB, Mundel P . Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. . J. Clin. Invest. . 108 . 11 . 1621–9 . 2002 . 11733557 . 200981 . 10.1172/JCI12849 .
• Koziell A, Grech V, Hussain S, Lee G, Lenkkeri U, Tryggvason K, Scambler P . Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. . Hum. Mol. Genet. . 11 . 4 . 379–88 . 2002 . 11854170 . 10.1093/hmg/11.4.379 . free .
• Yan K, Khoshnoodi J, Ruotsalainen V, Tryggvason K . N-linked glycosylation is critical for the plasma membrane localization of nephrin. . J. Am. Soc. Nephrol. . 13 . 5 . 1385–9 . 2002 . 11961028 . 10.1097/01.ASN.0000013297.11876.5B . free .
• Shimizu J, Tanaka H, Aya K, Ito S, Sado Y, Seino Y . A missense mutation in the nephrin gene impairs membrane targeting. . Am. J. Kidney Dis. . 40 . 4 . 697–703 . 2002 . 12324903 . 10.1053/ajkd.2002.35676 .
• Saleem MA, Ni L, Witherden I, Tryggvason K, Ruotsalainen V, Mundel P, Mathieson PW . Co-localization of nephrin, podocin, and the actin cytoskeleton: evidence for a role in podocyte foot process formation. . Am. J. Pathol. . 161 . 4 . 1459–66 . 2002 . 12368218 . 1867300 . 10.1016/S0002-9440(10)64421-5 .
• Kim BK, Hong HK, Kim JH, Lee HS . Differential expression of nephrin in acquired human proteinuric diseases. . Am. J. Kidney Dis. . 40 . 5 . 964–73 . 2002 . 12407641 . 10.1053/ajkd.2002.36328 .
• Langham RG, Kelly DJ, Cox AJ, Thomson NM, Holthöfer H, Zaoui P, Pinel N, Cordonnier DJ, Gilbert RE . Proteinuria and the expression of the podocyte slit diaphragm protein, nephrin, in diabetic nephropathy: effects of angiotensin converting enzyme inhibition. . Diabetologia . 45 . 11 . 1572–6 . 2003 . 12436341 . 10.1007/s00125-002-0946-y . free .
• Gigante M, Monno F, Roberto R, Laforgia N, Assael MB, Livolti S, Caringella A, La Manna A, Masella L, Iolascon A . Congenital nephrotic syndrome of the Finnish type in Italy: a molecular approach. . J. Nephrol. . 15 . 6 . 696–702 . 2003 . 12495287 .
• Pettersson-Fernholm K, Forsblom C, Perola M, Groop PH . Polymorphisms in the nephrin gene and diabetic nephropathy in type 1 diabetic patients. . Kidney Int. . 63 . 4 . 1205–10 . 2003 . 12631336 . 10.1046/j.1523-1755.2003.00855.x . free .
• Kapodistria K, Tsilibary EP, Politis P, Moustardas P, Charonis A, Kitsiou P . Nephrin, a transmembrane protein, is involved in pancreatic beta-cell survival signaling. . Mol. Cell. Endocrinol. . 400 . 112–28 . 2015 . 25448064 . 10.1016/j.mce.2014.11.003 . free .

Notes and References

1. Web site: Entrez Gene: NPHS1 nephrosis 1, congenital, Finnish type (nephrin).
2. Patrakka J, Tryggvason K. Nephrin – a unique structural and signaling protein of the kidney filter. Trends in Molecular Medicine. 2007. 13. 9. 396-403. 10.1016/j.molmed.2007.06.006. 17766183.
3. Martin CE, Jones N. Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond. Frontiers in Endocrinology. 2018. 9. Art. No. 302. 10.3389/fendo.2018.00302. free. 29922234. 5996060.
4. Menzel S, Moeller MJ. Role of the podocyte in proteinuria. 26. 1775-1780. 2011. Pediatric Nephrology. 10.1007/s00467-010-1725-5. free. 21184239. 3163769.
5. Wagner N, Morrison H, Pagnotta S, Michiels JF, Schwab Y, Tryggvason K, Schedl A, Wagner KD . The podocyte protein nephrin is required for cardiac vessel formation. . Human Molecular Genetics . 20 . 11 . 2182–94 . 2011-03-29 . 21402589 . 10.1093/hmg/ddr106 . free .
6. Lehtonen S, Lehtonen E, Kudlicka K, Holthöfer H, Farquhar MG . Nephrin forms a complex with adherens junction proteins and CASK in podocytes and in Madin-Darby canine kidney cells expressing nephrin . Am. J. Pathol. . 165 . 3 . 923–36 . Sep 2004 . 15331416 . 1618613 . 10.1016/S0002-9440(10)63354-8 .
7. Lahdenperä J, Kilpeläinen P, Liu XL, Pikkarainen T, Reponen P, Ruotsalainen V, Tryggvason K . Clustering-induced tyrosine phosphorylation of nephrin by Src family kinases . Kidney Int. . 64 . 2 . 404–13 . Aug 2003 . 12846735 . 10.1046/j.1523-1755.2003.00097.x . free .
8. Verma R, Wharram B, Kovari I, Kunkel R, Nihalani D, Wary KK, Wiggins RC, Killen P, Holzman LB . Fyn binds to and phosphorylates the kidney slit diaphragm component Nephrin . J. Biol. Chem. . 278 . 23 . 20716–23 . Jun 2003 . 12668668 . 10.1074/jbc.M301689200 . free .
9. Liu G, Kaw B, Kurfis J, Rahmanuddin S, Kanwar YS, Chugh SS . Neph1 and nephrin interaction in the slit diaphragm is an important determinant of glomerular permeability . J. Clin. Invest. . 112 . 2 . 209–21 . Jul 2003 . 12865409 . 164293 . 10.1172/JCI18242 .
10. Gerke P, Huber TB, Sellin L, Benzing T, Walz G . Homodimerization and heterodimerization of the glomerular podocyte proteins nephrin and NEPH1 . J. Am. Soc. Nephrol. . 14 . 4 . 918–26 . Apr 2003 . 12660326 . 10.1097/01.ASN.0000057853.05686.89 . free .
11. Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W, Shaw AS, Holzman LB, Mundel P . Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin . J. Clin. Invest. . 108 . 11 . 1621–9 . Dec 2001 . 11733557 . 200981 . 10.1172/JCI12849 .