Growing evidence suggests that there are many common cell biological features shared by neurons and podocytes; however, the mechanism of podocyte foot process formation remains unclear. Comparing the mechanisms of process formation between two cell types should provide useful guidance from the progress of neuron research. Studies have shown that some mature proteins of podocytes, such as podocin, nephrin, and synaptopodin, were also expressed in neurons. In this study, using cell biological experiments and immunohistochemical techniques, we showed that some neuronal iconic molecules, such as Neuron-specific enolase, nestin and Neuron-specific nuclear protein, were also expressed in podocytes. We further inhibited the expression of Neuron-specific enolase, nestin, synaptopodin and Ubiquitin carboxy terminal hydrolase-1 by Small interfering RNA in cultured mouse podocytes and observed the significant morphological changes in treated podocytes. When podocytes were treated with Adriamycin, the protein expression of Neuron-specific enolase, nestin, synaptopodin and Ubiquitin carboxy terminal hydrolase-1 decreased over time. Meanwhile, the morphological changes in the podocytes were consistent with results of the Small interfering RNA treatment of these proteins. The data demonstrated that neuronal iconic proteins play important roles in maintaining and regulating the formation and function of podocyte processes.
References
[1]
Kang Yl, Zhu Gh, He Wx (2009) Adaptive Reaction of Actin Cytoskeleton in Podocyte Structure of Glomerulus. J Appl Clin Pediatr 24: 383–385.
[2]
Kobayashi N, Mundel P (1998) A role of microtubules during the formation of cell processes in neuronal and non-neuronal cells. Cell Tissue Res 291: 163–174. doi: 10.1007/s004410050988
[3]
Kobayashi N, Gao SY, Chen J, Saito K, Miyawaki K, et al. (2004) Process formation of the renal glomerular podocyte: is there common molecular machinery for processes of podocytes and neurons? Anat Sci Int 79: 1–10. doi: 10.1111/j.1447-073x.2004.00066.x
[4]
Deller T, Mundel P, Frotscher M (2000) Potential role of synaptopodin in spine motility by coupling actin to the spine apparatus. Hippocampus 10: 569–581. doi: 10.1002/1098-1063(2000)10:5<569::aid-hipo7>3.3.co;2-d
[5]
Moeller MJ, Kovari IA, Holzman LB (2000) Evaluation of a new tool for exploring podocyte biology: mouse Nphs1 5' flanking region drives LacZ expression in podocytes. J Am Soc Nephrol 11: 2306–2314.
[6]
Putaala H, Soininen R, Kilpelainen P, Wartiovaara J, Tryggvason K (2001) The murine nephrin gene is specifically expressed in kidney, brain and pancreas: inactivation of the gene leads to massive proteinuria and neonatal death. Hum Mol Genet 10: 1–8. doi: 10.1093/hmg/10.1.1
[7]
Mundel P, Heid HW, Mundel TM, Kruger M, Reiser J, et al. (1997) Synaptopodin: an actin-associated protein in telencephalic dendrites and renal podocytes. J Cell Biol 139: 193–204. doi: 10.1083/jcb.139.1.193
[8]
Deller T, Merten T, Roth SU, Mundel P, Frotscher M (2000) Actin-associated protein synaptopodin in the rat hippocampal formation: localization in the spine neck and close association with the spine apparatus of principal neurons. J Comp Neurol 418: 164–181. doi: 10.1002/(sici)1096-9861(20000306)418:2<164::aid-cne4>3.0.co;2-0
[9]
Wilkinson KD, Lee KM, Deshpande S, Duerksen-Hughes P, Boss JM, et al. (1989) The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. Science 246: 670–673. doi: 10.1126/science.2530630
[10]
Saigoh K, Wang YL, Suh JG, Yamanishi T, Sakai Y, et al. (1999) Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nat Genet 23: 47–51.
[11]
Susor A, Ellederova Z, Jelinkova L, Halada P, Kavan D, et al. (2007) Proteomic analysis of porcine oocytes during in vitro maturation reveals essential role for the ubiquitin C-terminal hydrolase-L1. Reproduction 134: 559–568. doi: 10.1530/rep-07-0079
[12]
Shirato I, Asanuma K, Takeda Y, Hayashi K, Tomino Y (2000) Protein gene product 9.5 is selectively localized in parietal epithelial cells of Bowman's capsule in the rat kidney. J Am Soc Nephrol 11: 2381–2386.
[13]
Lowe J, McDermott H, Landon M, Mayer RJ, Wilkinson KD (1990) Ubiquitin carboxyl-terminal hydrolase (PGP 9.5) is selectively present in ubiquitinated inclusion bodies characteristic of human neurodegenerative diseases. J Pathol 161: 153–160. doi: 10.1002/path.1711610210
[14]
Choi J, Levey AI, Weintraub ST, Rees HD, Gearing M, et al. (2004) Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases. J Biol Chem 279: 13256–13264. doi: 10.1074/jbc.m314124200
[15]
Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, et al. (2006) Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory. Cell 126: 775–788. doi: 10.1016/j.cell.2006.06.046
[16]
Liu Y, Wu J, Wu H, Wang T, Gan H, et al. (2009) UCH-L1 expression of podocytes in diseased glomeruli and in vitro. J Pathol 217: 642–653. doi: 10.1002/path.2511
[17]
Meyer-Schwesinger C, Meyer TN, Sievert H, Hoxha E, Sachs M, et al. (2011) Ubiquitin C-terminal hydrolase-l1 activity induces polyubiquitin accumulation in podocytes and increases proteinuria in rat membranous nephropathy. Am J Pathol 178: 2044–2057. doi: 10.1016/j.ajpath.2011.01.017
[18]
Sakurai M, Ayukawa K, Setsuie R, Nishikawa K, Hara Y, et al. (2006) Ubiquitin C-terminal hydrolase L1 regulates the morphology of neural progenitor cells and modulates their differentiation. J Cell Sci 119: 162–171. doi: 10.1242/jcs.02716
[19]
Jia R, Hong X, Li S, Haichun Y, Chuanming H (2010) Expression of angiopoietin-like 3 associated with puromycin-induced podocyte damage. Nephron Exp Nephrol 115: e38–45. doi: 10.1159/000313829
[20]
Meyer-Schwesinger C, Meyer TN, Munster S, Klug P, Saleem M, et al. (2009) A new role for the neuronal ubiquitin C-terminal hydrolase-L1 (UCH-L1) in podocyte process formation and podocyte injury in human glomerulopathies. J Pathol 217: 452–464. doi: 10.1002/path.2446
[21]
Wiggins RC (2007) The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney Int 71: 1205–1214. doi: 10.1038/sj.ki.5002222
[22]
Kriz W, LeHir M (2005) Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int 67: 404–419. doi: 10.1111/j.1523-1755.2005.67097.x
[23]
Shirato I, Sakai T, Kimura K, Tomino Y, Kriz W (1996) Cytoskeletal changes in podocytes associated with foot process effacement in Masugi nephritis. Am J Pathol 148: 1283–1296.
[24]
Ruotsalainen V, Ljungberg P, Wartiovaara J, Lenkkeri U, Kestila M, et al. (1999) Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc Natl Acad Sci U S A 96: 7962–7967. doi: 10.1073/pnas.96.14.7962
[25]
Siu B, Saha J, Smoyer WE, Sullivan KA, Brosius FC 3rd (2006) Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: prevention by lipoic acid treatment. BMC Nephrol 7: 6.
[26]
Wang G, Lai FM, Lai KB, Chow KM, Li KT, et al. (2007) Messenger RNA expression of podocyte-associated molecules in the urinary sediment of patients with diabetic nephropathy. Nephron Clin Pract 106: c169–179. doi: 10.1159/000104428
[27]
Tan H, Fu S, Yang L (2008) Study of valsartan combined with benazepril on podocyte injury and renal protection mechanism in diabetic rats. Chinese Journal of Integrated Traditional and Western Nephrology 09: 6.
[28]
Mundel P, Reiser J, Zuniga Mejia Borja A, Pavenstadt H, Davidson GR, et al. (1997) Rearrangements of the cytoskeleton and cell contacts induce process formation during differentiation of conditionally immortalized mouse podocyte cell lines. Exp Cell Res 236: 248–258. doi: 10.1006/excr.1997.3739
[29]
Mundel P, Gilbert P, Kriz W (1991) Podocytes in glomerulus of rat kidney express a characteristic 44 KD protein. J Histochem Cytochem 39: 1047–1056. doi: 10.1177/39.8.1856454
[30]
Yang Q, Wang JG, Pan T, Ma L, Zhou Zl (2004) Expression of Synaptopodin in Glomerularlesions. Chinese Journal of Histochemistry and Cytochemistry 39.
[31]
Huber TB, Kwoh C, Wu H, Asanuma K, Godel M, et al. (2006) Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin. J Clin Invest 116: 1337–1345. doi: 10.1172/jci27400
[32]
George B, Holzman LB (2012) Signaling from the podocyte intercellular junction to the actin cytoskeleton. Semin Nephrol 32: 307–318. doi: 10.1016/j.semnephrol.2012.06.002
[33]
Wen Yq, Yu L, Wen J, Hao Zh, Chen Ry, et al. (2008) Distribution and Expression of Podocin in Puromye in Aminonueleoside Injured Mouse Podocyte Cell Line. Chin J Obs/Gyne &Pediatr (Electronic Version) 04.
[34]
Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT Jr (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell 111: 209–218. doi: 10.1016/s0092-8674(02)01012-7
[35]
Lansbury PT Jr (2006) Improving synaptic function in a mouse model of AD. Cell 126: 655–657. doi: 10.1016/j.cell.2006.08.011
[36]
Berger RP, Pierce MC, Wisniewski SR, Adelson PD, Clark RS, et al. (2002) Neuron-specific enolase and S100B in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatrics 109: E31. doi: 10.1542/peds.109.2.e31
[37]
Hardemark HG, Ericsson N, Kotwica Z, Rundstrom G, Mendel-Hartvig I, et al. (1989) S-100 protein and neuron-specific enolase in CSF after experimental traumatic or focal ischemic brain damage. J Neurosurg 71: 727–731. doi: 10.3171/jns.1989.71.5.0727
[38]
Brady ST, Lasek RJ (1981) Nerve-specific enolase and creatine phosphokinase in axonal transport: soluble proteins and the axoplasmic matrix. Cell 23: 515–523. doi: 10.1016/0092-8674(81)90147-1
[39]
Vinores SA, Herman MM, Rubinstein LJ, Marangos PJ (1984) Electron microscopic localization of neuron-specific enolase in rat and mouse brain. J Histochem Cytochem 32: 1295–1302. doi: 10.1177/32.12.6389693
[40]
Vinores SA, Herman MM, Rubinstein LJ (1986) Electron-immunocytochemical localization of neuron-specific enolase in cytoplasm and on membranes of primary and metastatic cerebral tumours and on glial filaments of glioma cells. Histopathology 10: 891–908. doi: 10.1111/j.1365-2559.1986.tb02588.x
[41]
Li Jc, Ding Pp, Liu Zc, Zhang J, Liang N, et al. (2010) Expression of nestin of neural precursor cell after spinal cord injury in rats. Chinese Journal of Rehabilitation Medicine 25: 833–837.
[42]
Duggal N, Schmidt-Kastner R, Hakim AM (1997) Nestin expression in reactive astrocytes following focal cerebral ischemia in rats. Brain Res 768: 1–9. doi: 10.1016/s0006-8993(97)00588-x
[43]
Krum JM, Rosenstein JM (1999) Transient coexpression of nestin, GFAP, and vascular endothelial growth factor in mature reactive astroglia following neural grafting or brain wounds. Exp Neurol 160: 348–360. doi: 10.1006/exnr.1999.7222
[44]
Cameron HA, Tanapat P, Gould E (1998) Adrenal steroids and N-methyl-D-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common pathway. Neuroscience 82: 349–354. doi: 10.1016/s0306-4522(97)00303-5
[45]
Gould E, Tanapat P (1997) Lesion-induced proliferation of neuronal progenitors in the dentate gyrus of the adult rat. Neuroscience 80: 427–436. doi: 10.1016/s0306-4522(97)00127-9
[46]
Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, et al. (1997) Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17: 3727–3738.
[47]
Cartier AE, Djakovic SN, Salehi A, Wilson SM, Masliah E, et al. (2009) Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1. J Neurosci 29: 7857–7868. doi: 10.1523/jneurosci.1817-09.2009
[48]
Deller T, Korte M, Chabanis S, Drakew A, Schwegler H, et al. (2003) Synaptopodin-deficient mice lack a spine apparatus and show deficits in synaptic plasticity. Proc Natl Acad Sci U S A 100: 10494–10499. doi: 10.1073/pnas.1832384100
[49]
Bertelli E, Regoli M, Fonzi L, Occhini R, Mannucci S, et al. (2007) Nestin expression in adult and developing human kidney. J Histochem Cytochem 55: 411–421. doi: 10.1369/jhc.6a7058.2007
