New Perspectives on the Renal Slit Diaphragm Protein Podocin

Overview

Journal Mod Pathol

Specialty Pathology

Date 2011 Apr 19

PMID 21499232

Citations 13

Authors

Manfred Relle

Hannes Cash

Christoph Brochhausen

Dennis Strand

Julia Menke

Peter R Galle

Andreas Schwarting

Affiliations

Soon will be listed here.

Abstract

Podocin is a critical component of the glomerular filtration barrier, its mutations causing recessive steroid-resistant nephrotic syndrome. A GenBank analysis of the human podocin (NPHS2) gene resulted in the possible existence of a new splice variant of podocin in the kidney, missing the in-frame of exon 5, encoding the prohibitin homology domain. Using RT-polymerase chain reaction and immunoblotting followed by sequence analysis, we are for the first time able to prove the expression of a novel podocin isoform (isoform 2), exclusively and constitutively expressed in human podocytes. Furthermore, we reveal singular extrarenal podocin expression in human and murine testis. Our data show the Sertoli cells of the seminiferous tubules to be the origin of testicular podocin. Confocal laser microscopy illustrates the co-localization of podocin with filamentous actin within Sertoli cells, suggesting a role of podocin in the blood/testis barrier. These results led to the rationale to examine podocin expression in testes of men with Sertoli cell-only syndrome, a disorder characterized by azoospermia. Interestingly, we observed a complete down-regulation of podocin mRNA in Sertoli cell-only syndrome, indicating a possible role of podocin in the pathogenesis of this germinal aplasia. Men with Sertoli cell-only syndrome show normal renal podocin expression, suggesting an alternate regulation of the testicular promoter. Our findings may change the perception of podocin and give new insights into the ultrastructure of glomerular slit diaphragm and the blood/testis barrier.

Citing Articles

METTL10 attenuates adriamycin-induced podocyte injury by targeting cell dedifferentiation.

Bao J, Li Z, Yao H, Wu B, Gu L, Pan Y Sci Rep. 2025; 15(1):1218.

PMID: 39774961 PMC: 11707283. DOI: 10.1038/s41598-024-80526-8.

Adult Mouse Kidney Stem Cells Orchestrate the De Novo Assembly of a Nephron via Sirt2-Modulated Canonical Wnt/β-Catenin Signaling.

Han X, Sun Z Adv Sci (Weinh). 2022; 9(15):e2104034.

PMID: 35315252 PMC: 9130916. DOI: 10.1002/advs.202104034.

Peptide Charge Derivatization as a Tool for Early Detection of Preeclampsia by Mass Spectrometry-A Comparison with the ELISA Test.

Grocholska P, Konieczny A, Kazmierczak Z, Dabrowska K, Panek-Laszczynska K, Klak M Molecules. 2021; 26(23).

PMID: 34885683 PMC: 8659024. DOI: 10.3390/molecules26237102.

Case Report: The Monogenic Familial Steroid-Resistant Nephrotic Syndrome Caused by a Novel Missense Mutation of Gene A593C in a Chinese Family.

Bai L, Zhuang J, Zhang C, Lu C, Tian X, Jiang H Front Pediatr. 2021; 9:692727.

PMID: 34631609 PMC: 8497038. DOI: 10.3389/fped.2021.692727.

Detection of Podocin in Human Urine Sediment Samples by Charge Derivatization and LC-MS-MRM Method.

Bachor R, Gaszczyk D, Panek-Laszczynska K, Konieczny A, Witkiewicz W, Stefanowicz P Int J Mol Sci. 2020; 21(9).

PMID: 32370166 PMC: 7247335. DOI: 10.3390/ijms21093225.

References

Lassila M, Juhila J, Heikkila E, Holthofer H . Densin is a novel cell membrane protein of Sertoli cells in the testis. Mol Reprod Dev. 2006; 74(5):641-5. DOI: 10.1002/mrd.20659. View

Relle M, Mayet W, Strand D, Brenner W, Galle P, Schwarting A . Proteinase 3/myeloblastin as a growth factor in human kidney cells. J Nephrol. 2004; 16(6):831-40. View

Benzing T . Signaling at the slit diaphragm. J Am Soc Nephrol. 2004; 15(6):1382-91. DOI: 10.1097/01.asn.0000130167.30769.55. View

Huber T, Schermer B, Muller R, Hohne M, Bartram M, Calixto A . Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels. Proc Natl Acad Sci U S A. 2006; 103(46):17079-86. PMC: 1859892. DOI: 10.1073/pnas.0607465103. View

Liu L, Aya K, Tanaka H, Shimizu J, Ito S, Seino Y . Nephrin is an important component of the barrier system in the testis. Acta Med Okayama. 2001; 55(3):161-5. DOI: 10.18926/AMO/32022. View

Reiser J, Polu K, Moller C, Kenlan P, Altintas M, Wei C . TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. 2005; 37(7):739-44. PMC: 1360984. DOI: 10.1038/ng1592. View

Simons K, Toomre D . Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2001; 1(1):31-9. DOI: 10.1038/35036052. View

Mundel P, Reiser J, Kriz W . Induction of differentiation in cultured rat and human podocytes. J Am Soc Nephrol. 1997; 8(5):697-705. DOI: 10.1681/ASN.V85697. View

Lee N, Cheng C . Ectoplasmic specialization, a testis-specific cell-cell actin-based adherens junction type: is this a potential target for male contraceptive development?. Hum Reprod Update. 2004; 10(4):349-69. DOI: 10.1093/humupd/dmh026. View

10.

Morrow I, Parton R . Flotillins and the PHB domain protein family: rafts, worms and anaesthetics. Traffic. 2005; 6(9):725-40. DOI: 10.1111/j.1600-0854.2005.00318.x. View

11.

Yan H, Cheng C . Blood-testis barrier dynamics are regulated by an engagement/disengagement mechanism between tight and adherens junctions via peripheral adaptors. Proc Natl Acad Sci U S A. 2005; 102(33):11722-7. PMC: 1183102. DOI: 10.1073/pnas.0503855102. View

12.

Niaudet P . Podocin and nephrotic syndrome: implications for the clinician. J Am Soc Nephrol. 2004; 15(3):832-4. DOI: 10.1097/01.asn.0000118135.00519.b0. View

13.

Huang M, Gu G, Ferguson E, Chalfie M . A stomatin-like protein necessary for mechanosensation in C. elegans. Nature. 1995; 378(6554):292-5. DOI: 10.1038/378292a0. View

14.

Thomaidis T, Relle M, Golbas M, Brochhausen C, Galle P, Beck M . Downregulation of alpha-galactosidase A upregulates CD77: functional impact for Fabry nephropathy. Kidney Int. 2008; 75(4):399-407. DOI: 10.1038/ki.2008.576. View

15.

Saleem M, Ni L, Witherden I, Tryggvason K, Ruotsalainen V, Mundel P . Co-localization of nephrin, podocin, and the actin cytoskeleton: evidence for a role in podocyte foot process formation. Am J Pathol. 2002; 161(4):1459-66. PMC: 1867300. DOI: 10.1016/S0002-9440(10)64421-5. View

16.

Schwarz K, Simons M, Reiser J, Saleem M, Faul C, Kriz W . Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest. 2001; 108(11):1621-9. PMC: 200981. DOI: 10.1172/JCI12849. View

17.

Mundlos S, Pelletier J, Darveau A, Bachmann M, Winterpacht A, Zabel B . Nuclear localization of the protein encoded by the Wilms' tumor gene WT1 in embryonic and adult tissues. Development. 1993; 119(4):1329-41. DOI: 10.1242/dev.119.4.1329. View

18.

Guo J, Menke A, Gubler M, Clarke A, Harrison D, Hammes A . WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis. Hum Mol Genet. 2002; 11(6):651-9. DOI: 10.1093/hmg/11.6.651. View

19.

Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A . NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet. 2000; 24(4):349-54. DOI: 10.1038/74166. View

20.

Kuusniemi A, Kestila M, Patrakka J, Lahdenkari A, Ruotsalainen V, Holmberg C . Tissue expression of nephrin in human and pig. Pediatr Res. 2004; 55(5):774-81. DOI: 10.1203/01.PDR.0000117842.10241.2C. View