ПАТОЛОГИЯ ПОДОЦИТОВ И НЕФРОПАТИЯ - РОЛЬ СФИНГОЛИПИДОВ В ГЛОМЕРУЛЯРНЫХ БОЛЕЗНЯХ

Сфинголипиды - это компоненты липидного слоя плазматической мембраны, которые необходимы для правильного функционирования подоцитов и являются ключевым элементом барьера клубочковой фильтрации. Выявлена важная роль сфинголипидов и их метаболитов при патологии клубочков генетического и негенетического происхождения. Открытие, что глюкоцереброзиды накапливаются при болезни Гоше в гломерулярных клетках и ассоциированы с протеинурией, инициировало интенсивные исследования, посвященные роли других сфинголипидов при патологии клубочков. Обсуждаются накопления сфинголипидов и их роль при гломерулярной патологии при других генетических заболеваниях, включая болезни Тея-Сакса, Сандхоффа, Фабри, наследственную миопатию с включениями, болезнь Ниманна-Пика и нефротический синдром финского типа. Накопление сфинголипидов происходит также при гломерулярных заболеваниях негенетического происхождения, включая диабетическую болезнь почек (ДБП), ВИЧ-ассоциированную нефропатию, фокально-сегментарный гломерулосклероз (ФСГС) и волчаночный нефрит. Огромный интерес представляют также метаболиты сфингомиелина, такие как церамид, сфингозин и сфингозин-1-фосфат. Нами недавно было описано, что в подоцитах экспрессируется кислото-подобный сфингомиелин фосфодиэстеразы (SMPDL3b), где она модулирует активность кислой сфингомиелиназы и выступает в качестве главного модулятора сигнализирования опасности. Снижение экспрессии SMPDL3b в биоптате почки после реперфузии трансплантата у реципиентов с идиопатическим ФСГС коррелирует с рецидивом протеинурии как у пациентов, так и в экспериментальных моделях ксенотрансплантации. Повышенная экспрессия SMPDL3b ассоциирована с ДБП. В статье будет обсуждено значение различного уровня экспрессии SMPDL3b в подоцитах при этих болезнях в зависимости от патогенеза этих заболеваний. Наконец, будут обсуждаться роль сфинголипидов в формировании липидного слоя подоцитов и их вклад в поддержание функции щелевой диафрагмы в клубочке.

сфинголипид, подоцит, болезни почек, гломерулярные болезни, С1Ф, церамид

1. McIlwain H. The second thudichum lecture. Cerebral isolates and neurochemical discovery. Biochem Soc Trans 1975; (3): 579-590

2. Pavenstadt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev 2003; (83): 253-307

3. Somlo S, Mundel P. Getting a foothold in nephrotic syndrome. Nat Genet 2000; (24): 333-335

4. Faul C, Asanuma K, Yanagida-Asanuma E, Kim K, Mundel P. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol 2007; (17): 428-437

5. Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P, Putaala H, et al. Positionally cloned gene for a novel glomerular protein - nephrin - is mutated in congenital nephrotic syndrome. Mol Cell 1998; (1): 575-582

6. Boute N, Gribouval O, Roselli S et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 2000; (24):349-354

7. Li C, Ruotsalainen V, Tryggvason K et al. CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere. Am J Physiol Renal Physiol 2000; (279): 785-792

8. Winn MP, Conlon PJ, Lynn KL et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 2005; (308): 1801-1804

9. Kaplan JM, Kim SH, North KN et al. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 2000; (24): 251-256

10. Goni FM, Alonso A. Effects of ceramide and other simple sphingolipids on membrane lateral structure. Biochim Biophys Acta 2009; (1788): 169-177

11. van Blitterswijk WJ, van der Luit AH, Veldman RJ et al. Ceramide: second messenger or modulator of membrane structure and dynamics? Biochem J 2003; (369): 199-211

12. Zhang X Li X, Becker KA, Gulbins E. Ceramide-enriched membrane domains - structure and function. Biochim Biophys Acta 2009; (1788): 178-183

13. Olivera A, Spiegel S. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 1993; (365): 557-560

14. Kaipia A, Chun SY Eisenhauer K, Hsueh AJ. Tumor necrosis factor-alpha and its second messenger, ceramide, stimulate apoptosis in cultured ovarian follicles. Endocrinology 1996; (137): 4864-4870

15. Merrill AH. Ceramide: a new lipid «second messenger»? Nutr Rev 1992; (50): 78-80

16. Nagiec MM, Wei ls GB, Lester RL, Dickson RC. A suppressor gene that enables Saccharomyces cerevisiae to grow without making sphingolipids encodes a protein that resembles an Escherichia coli fatty acyltransferase. J Biol Chem 1993; (268): 22156-22163

17. Merrill AH Jr. De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J Biol Chem 2002; (277): 25843-25846

18. Mondai S, Mukhopadhyay C. Molecular level investigation of organization in ternary lipid bilayer: a computational approach. Langmuir 2008; (24): 10298-10305

19. Hall A, Rog T, Karttunen M, Vattulainen I. Role of glycolipids in lipid rafts: a view through atomistic molecular dynamics simulations with galactosylceramide. J Phys Chem B 2010; (114):7797-7807

20. Hakomori S. Bifunctional role of glycosphingolipids. Modulators for transmembrane signaling and mediators for cellular interactions. J Biol Chem 1990; (265): 18713-18716

21. Shayman JA, Radin NS. Structure and function of renal glycosphingolipids. Am J Physiol 1991; (260): 291-302

22. Iwamori M, Shimomura J, Tsuyuhara S, Nagai Y Gangliosides of various rat tissues: distribution of ganglio-N-tetraose-containing gangliosides and tissue-characteristic composition of gangliosides. J Biochem 1984; (95): 761-770

23. Saito M, Sugiyama K. Gangliosides in rat kidney: composition, distribution, and developmental changes. Arch Biochem Biophys 2001; (386): 11-16

24. Hoon DS, Okun E, Neuwirth H et al. Aberrant expression of gangliosides in human renal cell carcinomas. J Urol 1993; (150): 2013-2018

25. Reivinen J, Holthofer H, Miettinen A. A cell-type specific ganglioside of glomerular podocytes in rat kidney: an O-acetylated GD3. Kidney Int 1992; (42): 624-631

26. Holthofer H, Reivinen J, Miettinen A. Nephron segment and cell-type specific expression of gangliosides in the developing and adult kidney. Kidney Int 1994; (45): 123-130

27. Barton NW, Brady RO, Dambrosia JM et al. Replacement therapy for inherited enzyme deficiency - macrophage-targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med 1991; (324): 1464-1470

28. Barton NW, Furbish FS, Murray GJ et al. Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci U S A 1990; (87): 1913-1916

29. Weinreb NJ, Charrow J, Andersson HC et al. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher registry. Am J Med 2002; (113): 112-119

30. Lukina E, Watman N, Arreguin EA et al. A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1. Blood 2010; (116): 893-899

31. Chander PN, Nurse HM, Pirani CL. Renal involvement in adult Gaucher’s disease after splenectomy. Arch Pathol Lab Med 1979; (103): 440-445

32. Vaccaro AM, Motta M, Tatti M et al. Saposin C mutations in Gaucher disease patients resulting in lysosomal lipid accumulation, saposin C deficiency, but normal prosaposin processing and sorting. Hum Mol Genet 2010; (19): 2987-2997

33. Sun X Witte DP, Zamzow M et al. Combined saposin C and D deficiencies in mice lead to a neuronopathic phenotype, glucosylceramide and alpha-hydroxy ceramide accumulation, and altered prosaposin trafficking. Hum Mol Genet 2007; (16): 957-971

34. Sandhoff K, Andreae U, Jatzkewitz H. Deficient hexoza-minidase activity in an exceptional case of Tay-Sachs disease with additional storage of kidney globoside in visceral organs. Life Sci 1968; (7): 283-288

35. Tatematsu M, Imaida K, Ito N et al. Sandhoff disease. Acta Pathol Jpn 1981; (31): 503-512

36. Sango K, Yamanaka S, Hoffmann A et al. Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism. Nat Genet 1995; (11): 170-176

37. Nance CS, Klein CJ, Banikazemi M et al. Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome. Arch Neurol 2006; (63):453-457

38. Krüger R, Bruns K, Grünhage S et al. Determination of globotriaosylceramide in plasma and urine by mass spectrometry. Clin Chem Lab Med 2010; (48): 189-198

39. Young E, Mills K, Morris P et al. Is globotriaosylceramide a useful biomarker in Fabry disease? Acta Paediatr Suppl 2005; (94): 51-54; discussion 37-58

40. Gold H, Mirzaian M, Dekker N, et al. Quantification of globotriaosylsphingosine in plasma and urine of fabry patients by stable isotope ultraperformance liquid chromatography-tandem mass spectrometry. Clin Chem 2012; (59): 547-556

41. Auray-Blais C, Ntwari A, Clarke JT, et al. How well does urinary lyso-Gb3 function as a biomarker in Fabry disease? Clin Chim Acta 2010; (411): 1906-1914

42. Askari H, Kaneski CR, Semino-Mora C, et al. Cellular and tissue localization of globotriaosylceramide in Fabry disease. Virchows Arch 2007; (451): 823-834

43. Alroy J, Sabnis S, Kopp JB. Renal pathology in Fabry disease. J Am Soc Nephrol 2002; 13[Suppl 2]: 134-138

44. Thurberg BL, Rennke H, Colvin RB et al. Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int 2002; (62): 1933-1946

45. Najafian B, Svarstad E, Bostad L et al. Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease. Kidney Int 2011; (79): 663-670

46. Quinta R, Rodrigues D, Assunçâo M, et al. Reduced glucosylceramide in the mouse model of Fabry disease: correction by successful enzyme replacement therapy. Gene 2014; (536): 97-104

47. Prabakaran T, Nielsen R, Larsen JV, et al. Receptor-mediated endocytosis of alpha-galactosidase A in human podocytes in Fabry disease. PLoS One (2011) (6): 25-65.

48. Liebau MC, Braun F, Höpker K, et al. Dysregulated autophagy contributes to podocyte damage in Fabry’s disease. PLoS One 2013 (8): 635-636

49. Keppler OT, Hinderlich S, Langner J, et al. UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation. Science 1999; (284): 1372-1376

50. Galeano B, Klootwijk R, Manoli I et al. Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. J Clin Invest 2007; (117): 1585-1594

51. Ito M, Sugihara K, Asaka T et al. Glycoprotein hyposialylation gives rise to a nephrotic-like syndrome that is prevented by sialic acid administration in GNE V572L point-mutant mice. PLoS One 2012; (7): 29873

52. Samuelsson K, Zetterstrom R. Ceramides in a patient with lipogranulomatosis (Farber’s disease) with chronic course. Scand J Clin Lab Invest 1971; (27): 393-405

53. Brière J, Calman F, Lageron A et al. Adult Niemann-Pick disease: a 26 years follow-up. Report of a case with isolated visceral involvement, excess of tissue sphingomyelin, and deficient sphingomyelinase activity (author’s transl). Nouv Rev Fr Hematol Blood Cells 1976; (16): 185-202

54. Kuemmel TA, Thiele J, Schroeder R, Stoffel W. Pathology of visceral organs and bone marrow in an acid sphingomyelinase deficient knock-out mouse line, mimicking human Niemann-Pick disease type A. A light and electron microscopic study. Pathol Res Pract 1997; (193): 663-671

55. Miranda SR, He X, Simonaro CM, et al. Infusion of recombinant human acid sphingomyelinase into Niemann-pick disease mice leads to visceral, but not neurological, correction of the pathophysiology. FASEB J 2000; (14): 1988-1995

56. Haltia A, Solin ML, Jalanko H et al. Sphingolipid activator proteins in a human hereditary renal disease with deposition of disialogangliosides. Histochem J 1996; (28): 681-687

57. Tamaoki A, Kikkawa Y. The role of sulfatides in autoimmunity in children with various glomerular disease. Nihon Jinzo Gakkai Shi 1991; (33): 1045-1054

58. Twfeek DM, Zaki SM. Role of tumour necrosis factor alpha and CD95 as markers of apoptosis in pathogenesis of pediatrics renal diseases. Egypt J Immunol 2005; (12): 155-165

59. De Maria R, Lenti L, Malisan F et al. Requirement for GD3 ganglioside in CD95- and ceramide-induced apoptosis. Science 1997; (277): 1652-1655

60. De Maria R, Rippo MR, Schuchman EH, Testi R. Acidic sphingomyelinase (ASM) is necessary for fas-induced GD3 ganglioside accumulation and efficient apoptosis of lymphoid cells. J Exp Med 1998; (187): 897-902

61. Cifone MG, De Maria R, Roncaioli P et al. Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase. J Exp Med 1994; (180): 1547-1552

62. Omran OM, Saqr HE, Yates AJ. Molecular mechanisms of GD3-induced apoptosis in U-1242 MG glioma cells. Neurochem Res 2006; (31): 1171-1180

63. Wiegmann K, Schwandner R, Krut O et al. Requirement of FADD for tumor necrosis factor-induced activation of acid sphingomyelinase. J Biol Chem 1999; (274): 5267-5270.

64. Aguilar RP, Genta S, Sanchez S. Renal gangliosides are involved in lead intoxication. J Appl Toxicol 2008; (28): 122-131

65. Meyer TW, Bennett PH, Nelson RG. Podocyte number predicts long-term urinary albumin excretion in Pima Indians with type II diabetes and microalbuminuria. Diabetologia 1999; (42): 1341-1344

66. Steffes MW, Schmidt D, McCrery R, Basgen JM. Glomerular cell number in normal subjects and in type 1 diabetic patients. Kidney Int 2001; (59): 2104-2113

67. Verzola D, Gandolfo MT, Ferrario F et al. Apoptosis in the kidneys of patients with type II diabetic nephropathy. Kidney Int 2007; (10): 1262-1272

68. White KE, Bilous RW, Marshall SM et al. Podocyte number in normotensive type 1 diabetic patients with albuminuria. Diabetes 2002; (51): 3083-3089

69. Pagtalunan ME, Miller PL, Jumping-Eagle S et al. Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 1997; (99): 342-348

70. Kremer GJ, Atzpodien W, Schnellbacher E. Plasma glycosphingolipids in diabetics and normals. Klin Wochenschr 1975; (53): 637-638

71. Haus JM, Kashyap SR, Kasumov T et al. Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance. Diabetes 2009; (58): 337-343

72. Blachnio-Zabielska AU, Pulka M, Baranowski M et al. Ceramide metabolism is affected by obesity and diabetes in human adipose tissue. J Cell Physiol 2011; (227): 550-557

73. Gorska M, Dobrzyn A, Baranowski M. Concentrations of sphingosine and sphinganine in plasma of patients with type 2 diabetes. Med Sci Monit 2005; (11): 35-38.

74. Geoffroy K, Troncy L, Wiernsperger N et al. Glomerular proliferation during early stages of diabetic nephropathy is associated with local increase of sphingosine-1-phosphate levels. FEBS Lett 2005; (579): 1249-1254

75. Zador IZ, Deshmukh GD, Kunkel R et al. A role for glycosphingolipid accumulation in the renal hypertrophy of streptozoto-cin-induced diabetes mellitus. J Clin Invest 1993; (91): 797-803

76. Kwak DH, Rho YI, Kwon OD et al. Decreases of ganglioside GM3 in streptozotocin-induced diabetic glomeruli of rats. Life Sci 2003; (72): 1997-2006

77. Liu G, Han F, Yang Y et al. Evaluation of sphingolipid metabolism in renal cortex of rats with streptozotocin-induced diabetes and the effects of rapamycin. Nephrol Dial Transplant 2011; (26): 1493-1502

78. Yoo TH, Pedigo CE, Guzman J et al. SMPDL3b expression levels determine podocyte injury phenotypes in glomerular disease. J Am Soc Nephrol 2014 25[4]: 737-744

79. Brunskill EW, Potter SS. Changes in the gene expression programs of renal mesangial cells during diabetic nephropathy. BMC Nephrol 2012; (13):70

80. Ishizawa S, Takahashi-Fujigasaki J, Kanazawa Y et al. Sphingosine-1-phosphate induces differentiation of cultured renal tubular epithelial cells under Rho kinase activation via the S1P2 receptor. Clin Exp Nephrol 2014

81. Samad F, Hester KD, Yang G et al. Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk. Diabetes 2006; (55): 2579-2587

82. Holthofer H, Reivinen J, Solin ML et al. Decrease of glomerular disialogangliosides in puromycin nephrosis of the rat. Am J Pathol 1996; (149): 1009-15

83. Andrews PM. Glomerular epithelial alterations resulting from sialic acid surface coat removal. Kidney Int 1979; (15): 376-385

84. Pawluczyk IZ, Ghaderi Najafabadi M, Patel S et al. Sialic acid attenuates puromycin aminonucleoside-induced desialylation and oxidative stress in human podocytes. Exp Cell Res 2013; (320): 258-268

85. Barisoni L, Bruggeman LA, Mundel P et al. HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy. Kidney Int 2000; (58): 173-181

86. Bruggeman LA, Dikman S, Meng C, et al. Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression. J Clin Invest 1997; (100): 84-92

87. Mikulak J, Singhal PC. HIV-1 entry into human podocytes is mediated through lipid rafts. Kidney Int 2010; (77): 72-3; author reply 73-74

88. Kopp JB, Klotman ME, Adler SH et al. Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes. Proc Natl Acad Sci U S A 1992; (89): 1577-1581

89. Husain M, Gusella GL, Klotman ME et al. HIV-1 Nef induces proliferation and anchorage-independent growth in podocytes. J Am Soc Nephrol 2002; (13): 1806-1815

90. Kajiyama W, Kopp JB, Marinos NJ et al. Glomerulosclerosis and viral gene expression in HIV-transgenic mice: role of nef. Kidney Int 2000; (58): 1148-1159

91. Sunamoto M, Husain M, He JC et al. Critical role for Nef in HIV-1-induced podocyte dedifferentiation. Kidney Int 2003; (64) 1695-1701

92. Hanna Z, Priceputu E, Hu C, et al. HIV-1 Nef mutations abrogating downregulation of CD4 affect other Nef functions and show reduced pathogenicity in transgenic mice. Virology 2006; (346): 40-52

93. Kopp JB, Nelson GW, Sampath K et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 2011; (22): 2129-2137

94. Liu XH, Lingwood CA, Ray PE. Recruitment of renal tubular epithelial cells expressing verotoxin-1 (Stx1) receptors in HIV-1 transgenic mice with renal disease. Kidney Int 1999; (55): 554-561

95. Kitiyakara C, Eggers P, Kopp JB. Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. Am J Kidney Dis 2004; (44): 815-825

96. Baum MA. Outcomes after renal transplantation for FSGS in children. Pediatr Transplant 2004; (8): 329-333

97. Hubsch H, Montané B, Abitbol C et al. Recurrent focal glomerulosclerosis in pediatric renal allografts: the Miami experience. Pediatr Nephrol 2005; (20): 210-216

98. Senggutuvan P, Cameron JS, Hartley RB et al. Recurrence of focal segmental glomerulosclerosis in transplanted kidneys: analysis of incidence and risk factors in 59 allografts. Pediatr Nephrol 1990; (4):21-28

99. Fornoni A, Sageshima J, Wei C, et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med 2011; (3): 8546

100. Tasaki M, Shimizu A, Hanekamp I et al. Rituximab treatment prevents the earl y development of proteinuria following pig-to-baboon xeno-kidney transplantation. J Am Soc Nephrol 2014; (25): 737-744

101. Wei C, Möller CC, Altintas MM et al. Modification of kidney barrier function by the urokinase receptor. Nat Med 2008; (14): 55-63

102. Wei C, Trachtman H, Li J et al. Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol 2012; (23): 2051-2059

103. Merscher-Gomez S, Guzman J, Pedigo CE et al. Cyclodextrin protects podocytes in diabetic kidney disease. Diabetes 2013; 62[11]: 3817-3827

104. Pyne NJ, Long JS, Lee SC et al. New aspects of sphingosine 1-phosphate signaling in mammalian cells. Adv Enzyme Regul 2009; (49): 214-221

105. Rosen H, Goetzl EJ. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol 2005; (5): 560-570

106. Imasawa T, Kitamura H, Ohkawa R et al. Unbalanced expression of sphingosine 1-phosphate receptors in diabetic nephropathy. Exp Toxicol Pathol 2010; (62): 53-60

107. Koch A, Völzke A, Puff B et al. PPARgamma agonists upregulate sphingosine 1-phosphate (S1P) receptor 1 expression, which in turn reduces S1P-induced [Ca(2+)]i increases in renal mesangial cells. Biochim Biophys Acta 2013; (1831): 1634-1643

108. Awad AS, Rouse MD, Khutsishvili K et al. Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. Kidney Int 2011; (79): 1090-1098

109. Park SW, Kim M, Chen SW et al. Sphinganine-1-phosphate protects kidney and liver after hepatic ischemia and reperfusion in mice through S1P1 receptor activation. Lab Invest 2010; (90): 1209-1224

110. Kim M, Park SW, Pitson SM, Lee HT. Isoflurane protects human kidney proximal tubule cells against necrosis via sphin-gosine kinase and sphingosine-1-phosphate generation. Am J Nephrol 2010; (31):353-362

111. Awad AS, Ye H, Huang L, et al. Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney. Am J Physiol Renal Physiol 2006; (290): 1516-1524

112. Park SW, Kim M, D’Agati VD, Lee HT. Sphingosine kinase 1 protects against renal ischemia-reperfusion injury in mice by sphingosine-1-phosphate1 receptor activation. Kidney Int 2011; (80):1315-1327

113. Zager RA, Conrad S, Lochhead K et al. Altered sphingomyelinase and ceramide expression in the setting of ischemic and nephrotoxic acute renal failure. Kidney Int 1998; (53): 573-582

114. Kalhorn T, Zager RA. Renal cortical ceramide patterns during ischemic and toxic injury: assessments by HPLC-mass spectrometry. Am J Physiol 1999; (277): 723-733.

115. Zager RA, Iwata M, Conrad DS et al. Altered ceramide and sphingosine expression during the induction phase of ischemic acute renal failure. Kidney Int 1997; (52): 60-70

116. Peters H, Martini S, Wang Y et al. Selective lymphocyte inhibition by FTY720 slows the progressive course of chronic anti-thy 1 glomerulosclerosis. Kidney Int 2004; (66): 1434-1443

117. Martini S, Krämer S, Loof T, et al. S1P modulator FTY720 limits matrix expansion in acute anti-thy1 mesangioproliferative glomerulonephritis. Am J Physiol Renal Physiol 2007; (292): 1761-1770

118. Schwalm S, Pfeilschifter J, Huwiler A. Targeting the sphingosine kinase/sphingosine 1-phosphate pathway to treat chronic inflammatory kidney diseases. Basic Clin Pharmacol Toxicol 2014; (114): 44-49

119. Ferguson R. FTY720 immunomodulation: optimism for improved transplant regimens. Transplant Proc 2004; (36): 549-553

120. Fujishiro J, Kudou S, Iwai S et al. Use of sphingosine-1-phosphate 1 receptor agonist, KRP-203, in combination with a subtherapeutic dose of cyclosporine A for rat renal transplantation. Transplantation 2006; (82): 804-812

121. Watson L, Tullus K, Marks SD et al. Increased serum concentration of sphingosine-1-phosphate in juvenile-onset systemic lupus erythematosus. J Clin Immunol 2012; (32): 1019-1025

122. Snider AJ, Ruiz P, Obeid LM, Oates Jc. Inhibition of sphingosine kinase-2 in a murine model of lupus nephritis. PLoS One 2013; (8): 53521

123. Ruotsalainen V, Ljungberg P, Wartiovaara J et al. Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc Natl Acad Sci U S A 1999; (96): 7962-7967

124. Tryggvason K. Unraveling the mechanisms of glomerular ultrafiltration: nephrin, a key component of the slit diaphragm. J Am Soc Nephrol 1999; (10): 2440-2445

125. Saleem MA, O’Hare MJ, Reiser J et al. A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression. J Am Soc Nephrol 2002; (13): 630-638

126. Smoyer WE, Mundel P. Regulation of podocyte structure during the development of nephrotic syndrome. J Mol Med (Berl) 1998; (76): 172-183

127. Kerjaschki D. Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis. J Clin Invest 2001; (108): 1583-1587

128. Asanuma K, Mundel P. The role of podocytes in glomerular pathobiology. Clin Exp Nephrol 2003; (7): 255-259

129. Ichimura K, Kurihara H, Sakai T Actin filament organization of foot processes in rat podocytes. J Histochem Cytochem 2003; (51): 1589-1600

130. Ichimura K, Kurihara H, Sakai T Actin filament organization of foot processes in vertebrate glomerular podocytes. Cell Tissue Res 2007; (329): 541-557

131. Yuan H, Takeuchi E, Salant DJ. Podocyte slit-diaphragm protein nephrin is linked to the actin cytoskeleton. Am J Physiol Renal Physiol 2002; (282): 585-591

132. Huber TB, Simons M, Hartleben B et al. Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. Hum Mol Genet 2003; (12): 3397-3405

133. Huber TB, Kottgen M, Schilling B et al. Interaction with podocin facilitates nephrin signaling. J Biol Chem 2001; (276): 41543-41546

134. Fanning AS, Ma TY Anderson JM. Isolation and functional characterization of the actin binding region in the tight junction protein ZO-1. FASEB J 2002; (16): 1835-1837

135. Simons M, Schwarz K, Kriz W et al. Involvement of lipid rafts in nephrin phosphorylation and organization of the glomerular slit diaphragm. Am J Pathol 2001; (159): 1069-1077

136. Wang F, Nobes CD, Hall A, Spiegel S. Sphingosine 1-phosphate stimulates rho-mediated tyrosine phosphorylation of focal adhesion kinase and paxillin in Swiss 3T3 fibroblasts. Biochem J 1997; 324[Pt 2]: 481-488

137. Shabahang S, Liu YH, Huwiler A, Pfeilschifter J. Identification of the LIM kinase-1 as a ceramide-regulated gene in renal mesangial cells. Biochem Biophys Res Commun 2002; (298): 408-413

138. Takenouchi H, Kiyokawa N, Taguchi T et al. Shiga toxin binding to globotriaosyl ceramide induces intracellul ar signals that mediate cytoskeleton remodeling in human renal carcinoma-derived cells. J Cell Sci 2004; (117): 3911-3922

139. Jin J, Sison K, Li C et al. Soluble FLT1 binds lipid micro-domains in podocytes to control cell morphology and glomerular barrier function. Cell 2012; (151): 384-399