A Review on the Role of Actin Cytoskeleton genes of Podocytes in Childhood Nephrotic Syndrome
Main Article Content
Keywords
Nephrotic syndrome; Podocyte; Actin cytoskeleton; Actin-associated proteins
Abstract
Podocytes play an essential role in establishing the glomerular filtration barrier. Podocyte dysfunction is central to the underlying pathophysiology of many common glomerular diseases, including nephrotic syndrome (NS), which often incites a progression to chronic kidney disease, affecting millions of patients worldwide. The role of podocytes in the pathogenesis of NS is best characterized by the discovery of genetic mutations, many of which regulate the actin cytoskeleton. Podocytes rely on an intact actin cytoskeleton to stabilise their unique cellular architecture and functions such as motility, cell division, intracellular transport, cellular trafficking of cargo and organelles and cell junction formation for the sustained function of glomerular filtration. This review briefly highlights the recent findings on role of actin cytoskeleton and the actin-associated proteins that take part in the assembly, maintenance and disassembly of actin cytoskeleton.
References
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2. Huber TB, Benzing T. The slit diaphragm: a signaling platform to regulatepodocyte function. Curr Opin Nephrol Hypertens 2005;14:211–216.
3. Garg P. A review of podocyte biology. Am J Nephrol. 2018;47:3–13.
4. Daehn IS, Duffield JS. The glomerular filtration barrier: a structural target for novel kidney therapies. Nat Rev Drug Disc. 2021;20(10):770–788.
5. Lennon R, Randles MJ, Humphries MJ. The importance of podocyte adhesion for a healthy glomerulus. Front Endocrinol. 2014;5:160–1177.
6. Kriz W, Lemley KV. A potential role for mechanical forces in the detachment of podocytes and the progression of CKD. J Am Soc Nephrol. 2015;26:258–269.
7. Somlo S, Mundel P. Getting a foothold in nephrotic syndrome. Nat Genet. 2000;24:333–335.
8. Wharram BL, Goyal M, Wiggins JE, Sanden SK, Hussain S, Filipiak WE, Saunders TL, Dysko RC, Kohno K, Holzman LB, Wiggins RC: Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol 2005;16:2941–2952.
9. Trimarchi H. Podocyturia: What is in a name?. J Transl Intern Med 2015;3(2), 51–56.
10. Campbell KN, Tumlin JA. Protecting Podocytes: A key target for therapy of focal segmental glomerulosclerosis. Amer J Nephrol. 2018; 47 (1) 14–29.
11. Greka A, Mundel P. Cell biology and pathology of podocytes. Annu Rev Physiol. 2012; 74:299–323.
12. Blaine J, Dylewski J. Regulation of the actin cytoskeleton in podocytes. Cells 2020;9(7): 1700.
13. Orlando RA, Takeda T, Zak B, Schmieder S, Benoit VM, McQuistan T, Furthmayr H, Farquhar MG (2001) The glomerular epithelial cell anti-adhesin podocalyxin associates with the actin cytoskeleton through interactions with ezrin. J Am Soc Nephrol 12:1589–1598.
14. Pollard TD and Borisy GG. (2003). Cellular motility driven by assembly and disassembly of actin filaments. Cell;112(4), 453–465.
15. Schell and Huber, 2017) [20]. Schell C, Huber,TB. (2017). The evolving complexity of the podocyte cytoskeleton. J Amer Society Nephrol 28(11):3166–3174.
16. Svitkina T. The actin cytoskeleton and actin-based motility. Cold Spring Harb. Perspect. Biol. 2018;10(1):a018267.
17. Faul, 2014. The podocyte cytoskeleton: Key to a functioning glomerulus in health and disease. Liu Z-H, He JC (eds): Cell biology and pathology of podocyte. Contrib Nephrol. Basel, Karger, 2014, vol 183, pp 22–53.
18. Oh J, Reiser J, Mundel P. Dynamic (re)organization of the podocyte actin cytoskeleton in the nephrotic syndrome. Pediatr Nephrol (2004) 19:130–137.
19. Perico L, Conti S, Benigni A, Remuzzi G. Podocyte-actin dynamics in health and disease. Nat Rev Nephrol. 2016;12:692–710.
20. Kim JH, Konieczkowski M, Mukherjee A, Schechtman S, Khan S, Scheling JR, Ross MD, Bruggeman LA, Sedor JR. Podocyte injury induces nuclear translocation of WTIP via microtubule-dependent transport. J Biol Chem. 2010;285:9995–10004.
21. Campellone KG, Welch MD. A nucleator arms race. Cellular control of actin assembly. Nat Rev Mol Cell Biol. 2010;11:237–251.
22. Lee S.H., Dominguez R. Regulation of actin cytoskeleton dynamics in cells. Mol. Cells. 2010;29:311–325.
23. Ransom RF, Lam NG, Hallett MA et al. Glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization. Kidney Int 2005; 68: 2473–2483.
24. Michaud JLR, Chaisson KM, Parks RJ, Kennedy CRJ. FSGS-associated a-actinin-4 (K256E) impairs cytoskeletal dynamics in podocytes. Kid Intern. 2006;70:1054–1061.
25. Machuca E, Benoit G, Antignac C: Genetics of nephrotic syndrome: connecting molecular genetics to podocyte physiology. Hum Mol Genet 2009;18:R185–R194.
26. Patrakka J, Tryggvason K. New insights into the role of podocytes in proteinuria. Nat Rev Nephrol 2007;5:463-8.
27. Verma R, Kovari I, Soofi A. et al. Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization. J Clin Invest. 2006;116:1346–1359.
28. Jones N, Blasutig IM, Eremina V, Ruston JM, Bladt F, Li H, Huang H, Larose l, Li SS, Takano T, Quaggin SE, Pawson T. NCK adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Nature 2006;440:818–823.
29. Zhu J, Attias O, Aoudjit L, Jiang R, Kawachi H, Takano T: p21-activated kinases regulate actin remodeling in glomerular podocytes. Am J Physiol Renal Physiol. 2010;298:F951– F961.
30. Zhu J, Sun N, Aoudjit L, Li H, Kawachi H, Lemay S, Takano T. Nephrin mediates actin reorganization via phosphoinositide 3-kinase in podocytes. Kidney Int. 2008;73: 556-566.
31. Venkatareddy M, Cook L, Abuarquob K, Verma R, Garg P. Nephrin regulates lamellipodia formation by assembling a protein complex that includes Ship2, filamin and lamellipodin. PLoS One 2011;6:e28710.
32. Garg P, Verma R, Cook L, Soofi A, Venkatareddy M, George B, Mizuno K, Gurniak C, Witke W, Holzman LB: Actin-depolymerizing factor cofilin-1 is necessary in maintaining mature podocyte architecture. J Biol Chem. 2010;285:22676–22688.
33. Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodrguez-Pe ́rez JC, Allen PG, Beggs AH, Pollak MR. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet. 2000;24:251–256.
34. Gautel M, Djinović-Carugo K. The sarcomeric cytoskeleton: from molecules to motion. J Exp Biol. 219(2):135–145.
35. Otey CA, Carpen O. Alpha-actinin revisited: a fresh look at an old player. Cell Motil Cytoskeleton 2004; 58: 104–111.
36. Asanuma K, Kim K, Oh J et al. Synaptopodin regulates the actin-bundling activity of alpha-actinin in an isoform-specific manner. J Clin Invest 2005;115: 1188–1198
37. Rajfur Z, Roy P, Otey C et al. Dissecting the link between stress fibres and focal adhesions by CALI with EGFP fusion proteins. Nat Cell Biol 2002; 4: 286–293.
38. Fraley TS, Tran TC, Corgan AM et al. Phosphoinositide binding inhibits alpha-actinin bundling activity. J Biol Chem. 2003;278: 24039–24045.
39. Izaguirre G, Aguirre L, Hu YP et al. The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase. J Biol Chem. 2001; 276: 28676–28685
40. Furukawa R, Maselli A, Thomson SA et al. Calcium regulation of actin crosslinking is important for function of the actin cytoskeleton in Dictyostelium. J Cell Sci 2003; 116: 187–196.
41. Bartram MP, Habbig S, Pahmeyer C, et al. Three-layered proteomic characterization of a novel ACTN4 mutation unravels its pathogenic potential in FSGS. Hum Mol Genet. 2016;25:1152–1164.
42. Weins, A. Schlondorff JS, Nakamura F, Denker BM, Hartwig JH, Thomas P. Stossel TP, Martin R. Pollak MR. Disease-associated mutant α-actinin-4 reveals a mechanism for regulating its F-actin-binding affinity. Proc Natl Acad Sci USA. 2007;104:16080–16085.
43. Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O, Miner JH, Shaw AS Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science. 1999;286:312–315.
44. Roselli S, Heidet L, Sich M et al. Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol Cell Biol. 2004;24:550–560.
45. Kos CH, Le TC, Sinha S, et al. Mice deficient in alpha-actinin-4 have severe glomerular disease. J Clin Invest. 2003;111:1683–1690.
46. Van Duijn TJ, Anthony EC, Hensbergen PJ, Deelder AM, Hordijk PL: Rac1 recruits the adapter protein CMS/CD2AP to cell-cell contacts. J Biol Chem. 2010;285:20137–20146.
47. Yaddanapudi S, Altintas MM, Kistler AD, Fernandez I, Moller CC, Wei C, et al: CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival. J Clin Invest 2011;121:3965–39.
48. Akilesh S, Suleiman H, Yu H, Stander MC, Lavin P, Gbadegesin R, Antignac C, Pollak M, Kopp JB, Winn MP, Shaw AS: Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. J Clin Invest. 2011;121:4127–4137.
49. Dryer SE, Reiser J. TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology. Am J Physiol Renal Physiol. 2010;299:F689–F701.
50. Tian D, Jacobo SM, Billing D et al. Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels. Sci Signal 2010;3: ra77.
51. Huber TB, Schermer B, Benzing T. Podocin organizes ion channel-lipid super complexes: implications for mechanosensation at the slit diaphragm Nephron Exp Nephrol. 2007;106: e27-e31.
52. Mundel P, Heid HW, Mundel TM et al. Synaptopodin: an actin-associated protein intelencephalic dendrites and renal podocytes. J Cell Biol. 1997; 139: 193–204.
53. Patrie KM, Drescher AJ, Welihinda A et al. Interaction of two actin-binding proteins, synaptopodin and alpha-actinin-4, with the tight junction protein MAGI-1. J Biol Chem. 2002; 277: 30183–30190.
54. Asanuma K, Yanagida-Asanuma E, Faul C, Tomino Y, Kim K, Mundel P. Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nat Cell Biol. 2006;8:485–491.
55. Kemeny E, Durmuller U, Nickeleit V, Gudat F, Mihatsch MJ (1997) Distribution of podocyte protein (44 KD) in different types of glomerular diseases. Virchows Arch. 431:425–430.
56. Srivastava T, Garola RE, Whiting JM, Alon US. Synaptopodin expression in idiopathic nephrotic syndrome of childhood. Kidney Int. 2001;59:118–125.
57. Hegsted, A., Yingling, C. V., & Pruyne, D. (2017). Inverted formins: A subfamily of atypical formins. Cytoskeleton 74(11), 405–419.
58. Chhabra ES, Higgs HN. INF2 is a WASP homology 2 motif-containing formin that severs actin filaments and accelerates both polymerization and depolymerization. J Biol Chem. 2006;281(36):26754–67.
59. Sun H, Schlondorff J, Higgs HN, Pollak MR: Inverted formin 2 regulates actin dynamics by antagonizing Rho/diaphanous-related formin signaling. J Am Soc Nephrol. 2013; 24:917–929.
60. Rollason R, Wherlock M, Heath JA, Heesom KJ, Saleem MA, Welsh GI. Disease causing mutations in inverted formin 2 regulate its binding to G-actin, F-actin capping protein (CapZ alpha-1) and profilin 2. Biosci Rep. 2016;36:e00302.
61. Pollard TD. Regulation of actin filament assembly by Arp2/3 complex and formins. Annu Rev Biophys Biomol Struct. 2017;36:451–77.
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Jun 30, 2023
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Pricilla Charmine, Vettriselvi Venkatesan, Sangeetha Geminiganesan, Bollam Rangaswamy Nammalwar, & Mohanapriya Chinambedu Dandapani. (2023). A Review on the Role of Actin Cytoskeleton genes of Podocytes in Childhood Nephrotic Syndrome. Journal of Population Therapeutics and Clinical Pharmacology, 30(16), 330–341. https://doi.org/10.47750/jptcp.2023.30.16.045
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