Abstract
There have been many exciting advances in our understanding of genetic causes of nephrotic syndrome since 1998 when nephrin was first found. The mRNA expressions of nephrin and CD2AP were studied by quantitative real-time polymerase chain reaction (PCR) in aspirated renal biopsy tissues from 9 subjects with minimal change nephrotic syndrome (MCNS), 6 with primary IgA nephropathy (IgAN), and 15 controls. Protein expression of nephrin, podocin, and CD2AP were analyzed by immunohistochemistry, indirect immunofluorescence, and laser confocal microscope. Compared with controls, the CD2AP mRNA level was significantly downregulated in renal samples from MCNS and IgAN patients (p=0.001 in MCNS, p=0.046 in IgAN), though no significant downregulation was found in the mRNA level of nephrin (p=0.346 in MCNS, p=0.311 in IgAN). The expression levels of protein CD2AP and nephrin were significantly reduced in MCNS and IgAN (MCNS: nephrin, p=0.034, CD2AP, p=0.005; IgAN: nephrin, p=0.021, CD2AP, p=0.025). The podocin staining did not differ significantly between controls and disease groups (p value 0.340 and 0.787, respectively). The results suggest that transcript and translation expression changes of nephrin and CD2AP may have pathogenetic roles in some patients with MCNS and IgAN in Chinese, though no correlation was found in podocin with proteinuria in this study.
Similar content being viewed by others
References
Kestila M, Lenkkeri U, Mannikko 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 (1998) Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol Cell 1:575–582
Lenkkeri U, Mannikko M, McCready P, Lamerdin J, Gribouval O, Niaudet PM, Antignac CK, Kashtan CE, Holmberg C, Olsen A, Kestila M, Tryggvason K (1999) Structure of the gene for congenital nephrotic syndrome of the Finnish type (NPHS1) and characterization of mutations. Am J Hum Genet 64:51–61
Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24:349–354
Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O, Miner JH, Shaw AS (1999) Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286:312–315
Kim JM, Wu H, Green G, Winkler CA, Kopp JB, Miner JH, Unanue ER, Shaw AS (2003) CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science 300:1298–1300
Simons M, Schwarz K, Kriz W, Miettinen A, Reiser J, Mundel P, Holthofer H (2001) Involvement of lipid rafts in nephrin phosphorylation and organization of the glomerular slit diaphragm. Am J Pathol 159:1069–1077
Chugh SS, Kaw B, Kanwar YS (2003) Molecular structure-function relationship in the slit diaphragm. Semin Nephrol 23:544–555
Yuan H, Takeuchi E, Salant DJ (2002) Podocyte slit-diaphragm protein nephrin is linked to the actin cytoskeleton. Am J Physiol Renal Physiol 282:F585–F591
Akhtar M, Al Mana H (2004) Molecular basis of proteinuria. Adv Anat Pathol 11:304–309
Wartiovaara J, Ofverstedt LG, Khoshnoodi J, Zhang J, Makela E, Sandin S, Ruotsalainen V, Cheng RH, Jalanko H, Skoglund U, Tryggvason K (2004) Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography. J Clin Invest 114:1475–1483
Liu XL, Kilpelainen P, Hellman U, Sun Y, Wartiovaara J, Morgunova E, Pikkarainen T, Yan K, Jonsson AP, Tryggvason K (2005) Characterization of the interactions of the nephrin intracellular domain. FEBS J 272:228–243
Huber TB, Benzing T (2005) The slit diaphragm: a signaling platform to regulate podocyte function. Curr Opin Nephrol Hypertens 14:211–216
Schachter AD (2004) The pediatric nephrotic syndrome spectrum: clinical homogeneity and molecular heterogeneity. Pediatr Transplant 8:344–348
Koop K, Eikmans M, Baelde HJ, Kawachi H, De Heer E, Paul LC, Bruijn JA (2003) Expression of podocyte-associated molecules in acquired human kidney diseases. J Am Soc Nephrol 14:2063–2071
Furness PN, Hall LL, Shaw JA, Pringle JH (1999) Glomerular expression of nephrin is decreased in acquired human nephrotic syndrome. Nephrol Dial Transplant 14:1234–1237
Huh W, Kim DJ, Kim MK, Kim YG, Oh HY, Ruotsalainen V, Tryggvason K (2002) Expression of nephrin in acquired human glomerular disease. Nephrol Dial Transplant 17:478–484
Srivastava T, Whiting JM, Garola RE, Dasouki MJ, Ruotsalainen V, Tryggvason K, Hamed R, Alon US (2001) Podocyte proteins in Galloway-Mowat syndrome. Pediatr Nephrol 16:1022–1029
Wang SX, Rastaldi MP, Patari A, Ahola H, Heikkila E, Holthofer H (2002) Patterns of nephrin and a new proteinuria-associated protein expression in human renal diseases. Kidney Int 61:141–147
Doublier S, Ruotsalainen V, Salvidio G, Lupia E, Biancone L, Conaldi PG, Reponen P, Tryggvason K, Camussi G (2001) Nephrin redistribution on podocytes is a potential mechanism for proteinuria in patients with primary acquired nephrotic syndrome. Am J Pathol 158:1723–1731
Patrakka J, Ruotsalainen V, Ketola I, Holmberg C, Heikinheimo M, Tryggvason K, Jalanko H (2001) Expression of nephrin in pediatric kidney diseases. J Am Soc Nephrol 12:289–296
Guan N, Ding J, Zhang J, Yang J (2003) Expression of nephrin, podocin, alpha-actinin, and WT1 in children with nephrotic syndrome. Pediatr Nephrol 18:1122–1127
Hingorani SR, Finn LS, Kowalewska J, McDonald RA, Eddy AA (2004) Expression of nephrin in acquired forms of nephrotic syndrome in childhood. Pediatr Nephrol 19:300–305
Lahdenkari AT, Suvanto M, Kajantie E, Koskimies O, Kestila M, Jalanko H (2005) Clinical features and outcome of childhood minimal change nephrotic syndrome: is genetics involved? Pediatr Nephrol 20:1073–1080
Wernerson A, Duner F, Pettersson E, Widholm SM, Berg U, Ruotsalainen V, Tryggvason K, Hultenby K, Soderberg M (2003) Altered ultrastructural distribution of nephrin in minimal change nephrotic syndrome. Nephrol Dial Transplant 18:70–76
Salant DJ, Topham PS (2003) Role of nephrin in proteinuric renal diseases. Springer Semin Immunopathol 24:423–439
Kim BK, Hong HK, Kim JH, Lee HS (2002) Differential expression of nephrin in acquired human proteinuric diseases. Am J Kidney Dis 40:964–973
Gagliardini E, Benigni A, Tomasoni S, Abbate M, Kalluri R, Remuzzi G (2003) Targeted downregulation of extracellular nephrin in human IgA nephropathy. Am J Nephrol 23:277–286
Schmid H, Henger A, Cohen CD, Frach K, Grone HJ, Schlondorff D, Kretzler M (2003) Gene expression profiles of podocyte-associated molecules as diagnostic markers in acquired proteinuric diseases. J Am Soc Nephrol 14:2958–2966
Toyoda M, Suzuki D, Umezono T, Uehara G, Maruyama M, Honma M, Sakai T, Sakai H (2004) Expression of human nephrin mRNA in diabetic nephropathy. Nephrol Dial Transplant 19:380–385
Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH, Pollak MR (2000) Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24:251–256
Acknowledgements
This work was supported by the Zhejiang Provincial Natural Science Foundation of China No. 302656 and the Zhejiang provincial Health Science Foundation No. 2004QN014. The authors thank Wu Yedong, Sheng Zheng, and Yu Zhongsheng for their excellent technical assistance and Drs. Xia Yonghui, Huang Yaping, and Dai Yuwen for many helpful clinical comments and advice. The authors are also grateful to Drs. Wu Dehua and Zhang Chong for providing control kidney materials to us.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mao, J., Zhang, Y., Du, L. et al. Expression profile of nephrin, podocin, and CD2AP in Chinese children with MCNS and IgA nephropathy. Pediatr Nephrol 21, 1666–1675 (2006). https://doi.org/10.1007/s00467-006-0218-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-006-0218-z