Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

Pediatric Nephrology

Volumn 31, Issue 3, 2016, Pages 393-405

  Müller Deile, Janina ^a   Schiffer, Mario ^a  

^a HANNOVER MEDICAL SCHOOL   (Germany)

Author keywords

Actin cytoskeleton; Foot process effacement; Nephrotic syndrome; Podocyte; Treatment

Indexed keywords

ABATACEPT; AMILORIDE; CALCINEURIN INHIBITOR; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; GLUCOCORTICOID; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MANNOSAMINE; N ACETYL DEXTRO MANNOSAMINE; NOTCH RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PROTEIN KINASE C INHIBITOR; PROTEINASE INHIBITOR; RITUXIMAB; SMALL INTERFERING RNA; TRANSFORMING GROWTH FACTOR BETA ANTIBODY; TRANSIENT RECEPTOR POTENTIAL CHANNEL 6; UNCLASSIFIED DRUG; VASCULOTROPIN INHIBITOR; URINARY TRACT AGENT;

ACTIN FILAMENT; ARTICLE; CELL FUNCTION; DIABETIC NEPHROPATHY; DRUG MECHANISM; GLOMERULOPATHY; GLOMERULUS BASEMENT MEMBRANE; GLOMERULUS FILTRATION; HUMAN; KIDNEY HYPERTROPHY; NEPHROTIC SYNDROME; NONHUMAN; PERFUSION PRESSURE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PODOCYTE; PRIORITY JOURNAL; PROTEINURIA; RNA INTERFERENCE; T LYMPHOCYTE; ANIMAL; CYTOSKELETON; DRUG DEVELOPMENT; DRUG EFFECTS; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOLOGY; PROCEDURES; SIGNAL TRANSDUCTION;

ANIMALS; CYTOSKELETON; DRUG DISCOVERY; HUMANS; MOLECULAR TARGETED THERAPY; NEPHROTIC SYNDROME; PODOCYTES; RENAL AGENTS; SIGNAL TRANSDUCTION;

EID: 84958879730     PISSN: 0931041X     EISSN: 1432198X     Source Type: Journal    
DOI: 10.1007/s00467-015-3116-4     Document Type: Article

References (123)

1. Kim YH, Goyal M, Kurnit D, Wharram B, Wiggins J, Holzman L, Kershaw D, Wiggins R (2001) Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat. Kidney Int 60:957–968
2. Wharram BL, Goyal M, Wiggins JE, Sanden SK, Hussain S, Filipiak WE, Saunders TL, Dysko RC, Kohno K, Holzman LB, Wiggins RC (2005) Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol 16:2941–2952
3. Boehlke C, Hartleben B, Huber TB, Hopfer H, Walz G, Neumann-Haefelin E (2014) Hantavirus infection with severe proteinuria and podocyte foot-process effacement. Am J Kidney Dis 64:452–456
4. Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, Rastaldi MP, Calvaresi N, Watanabe H, Schwarz K, Faul C, Kretzler M, Davidson A, Sugimoto H, Kalluri R, Sharpe AH, Kreidberg JA, Mundel P (2004) Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest 113:1390–1397
5. Seiler MW, Venkatachalam MA, Cotran RS (1975) Glomerular epithelium: structural alterations induced by polycations. Science 189:390–393
6. Tossidou I, Himmelseher E, Teng B, Haller H, Schiffer M (2014) SUMOylation determines turnover and localization of nephrin at the plasma membrane. Kidney Int 86:1161–1173
7. Appel D, Kershaw DB, Smeets B, Yuan G, Fuss A, Frye B, Elger M, Kriz W, Floege J, Moeller MJ (2009) Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol 20:333–343
8. Shankland SJ, Anders HJ, Romagnani P (2013) Glomerular parietal epithelial cells in kidney physiology, pathology, and repair. Curr Opin Nephrol Hypertens 22:302–309
9. Lasagni L, Romagnani P (2010) Glomerular epithelial stem cells: the good, the bad, and the ugly. J Am Soc Nephrol 21:1612–1619
10. Berger K, Moeller MJ (2014) Podocytopenia, parietal epithelial cells and glomerulosclerosis. Nephrol Dial Transplant 29:948–950
11. Smeets B, Moeller MJ (2012) Parietal epithelial cells and podocytes in glomerular diseases. Semin Nephrol 32:357–367
12. Moeller MJ, Smeets B (2014) Role of parietal epithelial cells in kidney injury: the case of rapidly progressing glomerulonephritis and focal and segmental glomerulosclerosis. Nephron Exp Nephrol 126:97
13. Achenbach J, Mengel M, Tossidou I, Peters I, Park JK, Haubitz M, Ehrich JH, Haller H, Schiffer M (2008) Parietal epithelia cells in the urine as a marker of disease activity in glomerular diseases. Nephrol Dial Transplant 23:3138–3145
14. Hartleben B, Widmeier E, Suhm M, Worthmann K, Schell C, Helmstadter M, Wiech T, Walz G, Leitges M, Schiffer M, Huber TB (2013) aPKClambda/iota and aPKCzeta contribute to podocyte differentiation and glomerular maturation. J Am Soc Nephrol 24:253–267
15. Huber TB, Hartleben B, Winkelmann K, Schneider L, Becker JU, Leitges M, Walz G, Haller H, Schiffer M (2009) Loss of podocyte aPKClambda/iota causes polarity defects and nephrotic syndrome. J Am Soc Nephrol 20:798–806
16. Worthmann K, Leitges M, Teng B, Sestu M, Tossidou I, Samson T, Haller H, Huber TB, Schiffer M (2013) Def-6, a novel regulator of small GTPases in podocytes, acts downstream of atypical protein kinase C (aPKC) lambda/iota. Am J Pathol 183:1945–1959
17. Henderson JM, Alexander MP, Pollak MR (2009) Patients with ACTN4 mutations demonstrate distinctive features of glomerular injury. J Am Soc Nephrol 20:961–968
18. Gbadegesin RA, Hall G, Adeyemo A, Hanke N, Tossidou I, Burchette J, Wu G, Homstad A, Sparks MA, Gomez J, Jiang R, Alonso A, Lavin P, Conlon P, Korstanje R, Stander MC, Shamsan G, Barua M, Spurney R, Singhal PC, Kopp JB, Haller H, Howell D, Pollak MR, Shaw AS, Schiffer M, Winn MP (2014) Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS. J Am Soc Nephrol 25:1991–2002
19. 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
20. Suzuki K, Han GD, Miyauchi N, Hashimoto T, Nakatsue T, Fujioka Y, Koike H, Shimizu F, Kawachi H (2007) Angiotensin II type 1 and type 2 receptors play opposite roles in regulating the barrier function of kidney glomerular capillary wall. Am J Pathol 170:1841–1853
21. Gloy J, Henger A, Fischer KG, Nitschke R, Mundel P, Bleich M, Schollmeyer P, Greger R, Pavenstadt H (1997) Angiotensin II depolarizes podocytes in the intact glomerulus of the rat. J Clin Invest 99:2772–2781
22. Lapinski R, Perico N, Remuzzi A, Sangalli F, Benigni A, Remuzzi G (1996) Angiotensin II modulates glomerular capillary permselectivity in rat isolated perfused kidney. J Am Soc Nephrol 7:653–660
23. Sharma R, Lovell HB, Wiegmann TB, Savin VJ (1992) Vasoactive substances induce cytoskeletal changes in cultured rat glomerular epithelial cells. J Am Soc Nephrol 3:1131–1138
24. Durvasula RV, Petermann AT, Hiromura K, Blonski M, Pippin J, Mundel P, Pichler R, Griffin S, Couser WG, Shankland SJ (2004) Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 65:30–39
25. Yoo TH, Li JJ, Kim JJ, Jung DS, Kwak SJ, Ryu DR, Choi HY, Kim JS, Kim HJ, Han SH, Lee JE, Han DS, Kang SW (2007) Activation of the renin-angiotensin system within podocytes in diabetes. Kidney Int 71:1019–1027
26. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. the collaborative study group. N Engl J Med 329:1456–1462
27. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, RENAAL Study Investigators (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869
28. Macconi D, Ghilardi M, Bonassi ME, Mohamed EI, Abbate M, Colombi F, Remuzzi G, Remuzzi A (2000) Effect of angiotensin-converting enzyme inhibition on glomerular basement membrane permeability and distribution of zonula occludens-1 in MWF rats. J Am Soc Nephrol 11:477–489
29. Davis BJ, Cao Z, de Gasparo M, Kawachi H, Cooper ME, Allen TJ (2003) Disparate effects of angiotensin II antagonists and calcium channel blockers on albuminuria in experimental diabetes and hypertension: potential role of nephrin. J Hypertens 21:209–216
30. Nagase M, Fujita T (2008) Aldosterone and glomerular podocyte injury. Clin Exp Nephrol 12:233–242
31. Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF (2009) Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 4:542–551
32. Muller M, Renkawitz R (1991) The glucocorticoid receptor. Biochim Biophys Acta 1088:171–182
33. Yan K, Kudo A, Hirano H, Watanabe T, Tasaka T, Kataoka S, Nakajima N, Nishibori Y, Shibata T, Kohsaka T, Higashihara E, Tanaka H, Watanabe H, Nagasawa T, Awa S (1999) Subcellular localization of glucocorticoid receptor protein in the human kidney glomerulus. Kidney Int 56:65–73
34. Ransom RF, Vega-Warner V, Smoyer WE, Klein J (2005) Differential proteomic analysis of proteins induced by glucocorticoids in cultured murine podocytes. Kidney Int 67:1275–1285
35. Yu-Shengyou LY (2013) Dexamethasone inhibits podocyte apoptosis by stabilizing the PI3K/Akt signal pathway. Biomed Res Int 2013:326986
36. Liu H, Gao X, Xu H, Feng C, Kuang X, Li Z, Zha X (2012) Alpha-actinin-4 is involved in the process by which dexamethasone protects actin cytoskeleton stabilization from adriamycin-induced podocyte injury. Nephrology (Carlton) 17:669–675
37. Fujiwara Y (1984) An ultrastructural study of the effect of the steroid in puromycin aminonucleoside nephrosis rats. Virchows Arch A Pathol Anat Histopathol 405:11–24
38. Trachtman H, Del Pizzo R, Valderrama E, Gauthier B (1990) The renal functional and structural consequences of corticosteroid and angiotensin-converting enzyme inhibitor therapy in chronic puromycin aminonucleoside nephropathy. Pediatr Nephrol 4:501–504
39. Waldman M, Crew RJ, Valeri A, Busch J, Stokes B, Markowitz G, D’Agati V, Appel G (2007) Adult minimal-change disease: clinical characteristics, treatment, and outcomes. Clin J Am Soc Nephrol 2:445–453
40. Crabtree GR, Olson EN (2002) NFAT signaling: choreographing the social lives of cells. Cell 109[Suppl]:S67–79
41. Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P (2008) The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 14:931–938
42. Charbit M, Gubler MC, Dechaux M, Gagnadoux MF, Grunfeld JP, Niaudet P (2007) Cyclosporin therapy in patients with alport syndrome. Pediatr Nephrol 22:57–63
43. Chen D, Jefferson B, Harvey SJ, Zheng K, Gartley CJ, Jacobs RM, Thorner PS (2003) Cyclosporine a slows the progressive renal disease of alport syndrome (X-linked hereditary nephritis): results from a canine model. J Am Soc Nephrol 14:690–698
44. Callis L, Vila A, Carrera M, Nieto J (1999) Long-term effects of cyclosporine A in alport’s syndrome. Kidney Int 55:1051–1056
45. Bensman A, Niaudet P (2010) Non-immunologic mechanisms of calcineurin inhibitors explain its antiproteinuric effects in genetic glomerulopathies. Pediatr Nephrol 25:1197–1199
46. Gellermann J, Stefanidis CJ, Mitsioni A, Querfeld U (2010) Successful treatment of steroid-resistant nephrotic syndrome associated with WT1 mutations. Pediatr Nephrol 25:1285–1289
47. Malina M, Cinek O, Janda J, Seeman T (2009) Partial remission with cyclosporine A in a patient with nephrotic syndrome due to NPHS2 mutation. Pediatr Nephrol 24:2051–2053
48. Ponticelli C (2010) Recurrence of focal segmental glomerular sclerosis (FSGS) after renal transplantation. Nephrol Dial Transplant 25:25–31
49. Ruggenenti P, Ruggiero B, Cravedi P, Vivarelli M, Massella L, Marasa M, Chianca A, Rubis N, Ene-Iordache B, Rudnicki M, Pollastro RM, Capasso G, Pisani A, Pennesi M, Emma F, Remuzzi G, Rituximab in Nephrotic Syndrome of Steroid-Dependent or Frequently Relapsing Minimal Change Disease Or Focal Segmental Glomerulosclerosis (NEMO) Study Group (2014) Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. J Am Soc Nephrol 25:850–863
50. Perosa F, Favoino E, Caragnano MA, Dammacco F (2006) Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible cross-reactivity with acid sphingomyelinase-like phosphodiesterase 3b precursor. Blood 107:1070–1077
51. Fornoni A, Sageshima J, Wei C, Merscher-Gomez S, Aguillon-Prada R, Jauregui AN, Li J, Mattiazzi A, Ciancio G, Chen L, Zilleruelo G, Abitbol C, Chandar J, Seeherunvong W, Ricordi C, Ikehata M, Rastaldi MP, Reiser J, 3rd Burke GW (2011) Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med 3:85ra46
52. Godel M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S, Debreczeni-Mor A, Lindenmeyer MT, Rastaldi MP, Hartleben G, Wiech T, Fornoni A, Nelson RG, Kretzler M, Wanke R, Pavenstadt H, Kerjaschki D, Cohen CD, Hall MN, Ruegg MA, Inoki K, Walz G, Huber TB (2011) Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest 121:2197–2209
53. Spirli C, Okolicsanyi S, Fiorotto R, Fabris L, Cadamuro M, Lecchi S, Tian X, Somlo S, Strazzabosco M (2010) Mammalian target of rapamycin regulates vascular endothelial growth factor-dependent liver cyst growth in polycystin-2-defective mice. Hepatology 51:1778–1788
54. Lee CH, Inoki K, Guan KL (2007) mTOR pathway as a target in tissue hypertrophy. Annu Rev Pharmacol Toxicol 47:443–467
55. Yang Y, Wang J, Qin L, Shou Z, Zhao J, Wang H, Chen Y, Chen J (2007) Rapamycin prevents early steps of the development of diabetic nephropathy in rats. Am J Nephrol 27:495–502
56. Vogelbacher R, Wittmann S, Braun A, Daniel C, Hugo C (2007) The mTOR inhibitor everolimus induces proteinuria and renal deterioration in the remnant kidney model in the rat. Transplantation 84:1492–1499
57. Letavernier E, Legendre C (2008) mToR inhibitors-induced proteinuria: mechanisms, significance, and management. Transplant Rev (Orlando) 22:125–130
58. Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida S, Blattner SM, Ikenoue T, Ruegg MA, Hall MN, Kwiatkowski DJ, Rastaldi MP, Huber TB, Kretzler M, Holzman LB, Wiggins RC, Guan KL (2011) mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest 121:2181–2196
59. Fogo AB (2011) The targeted podocyte. J Clin Invest 121:2142–2145
60. Muller-Krebs S, Weber L, Tsobaneli J, Kihm LP, Reiser J, Zeier M, Schwenger V (2013) Cellular effects of everolimus and sirolimus on podocytes. PLoS One 8:e80340
61. Sartelet H, Toupance O, Lorenzato M, Fadel F, Noel LH, Lagonotte E, Birembaut P, Chanard J, Rieu P (2005) Sirolimus-induced thrombotic microangiopathy is associated with decreased expression of vascular endothelial growth factor in kidneys. Am J Transplant 5:2441–2447
62. Sandhu S, Wiebe N, Fried LF, Tonelli M (2006) Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol 17:2006–2016
63. Douglas K, O’Malley PG, Jackson JL (2006) Meta-analysis: the effect of statins on albuminuria. Ann Intern Med 145:117–124
64. Oda H, Keane WF (1999) Recent advances in statins and the kidney. Kidney Int Suppl 71:S2–5
65. Whaley-Connell A, Habibi J, Nistala R, Cooper SA, Karuparthi PR, Hayden MR, Rehmer N, DeMarco VG, Andresen BT, Wei Y, Ferrario C, Sowers JR (2008) Attenuation of NADPH oxidase activation and glomerular filtration barrier remodeling with statin treatment. Hypertension 51:474–480
66. Liu J, Zhang B, Chai Y, Xu Y, Xing C, Wang X (2015) Fluvastatin attenuated the effect of expression of beta1 integrin in PAN-treated podocytes by inhibiting reactive oxygen species. Mol Cell Biochem 398(1–2):207–215
67. Shibata S, Nagase M, Fujita T (2006) Fluvastatin ameliorates podocyte injury in proteinuric rats via modulation of excessive rho signaling. J Am Soc Nephrol 17:754–764
68. Cormack-Aboud FC, Brinkkoetter PT, Pippin JW, Shankland SJ, Durvasula RV (2009) Rosuvastatin protects against podocyte apoptosis in vitro. Nephrol Dial Transplant 24:404–412
69. Sarafidis PA, Stafylas PC, Georgianos PI, Saratzis AN, Lasaridis AN (2010) Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a meta-analysis. Am J Kidney Dis 55:835–847
70. Kanjanabuch T, Ma LJ, Chen J, Pozzi A, Guan Y, Mundel P, Fogo AB (2007) PPAR-gamma agonist protects podocytes from injury. Kidney Int 71:1232–1239
71. Yang HC, Ma LJ, Ma J, Fogo AB (2006) Peroxisome proliferator-activated receptor-gamma agonist is protective in podocyte injury-associated sclerosis. Kidney Int 69:1756–1764
72. Liu HF, Guo LQ, Huang YY, Chen K, Tao JL, Li SM, Chen XW (2010) Thiazolidinedione attenuate proteinuria and glomerulosclerosis in adriamycin-induced nephropathy rats via slit diaphragm protection. Nephrology (Carlton) 15:75–83
73. Yuan Y, Huang S, Wang W, Wang Y, Zhang P, Zhu C, Ding G, Liu B, Yang T, Zhang A (2012) Activation of peroxisome proliferator-activated receptor-gamma coactivator 1alpha ameliorates mitochondrial dysfunction and protects podocytes from aldosterone-induced injury. Kidney Int 82:771–789
74. Agrawal S, Guess AJ, Benndorf R, Smoyer WE (2011) Comparison of direct action of thiazolidinediones and glucocorticoids on renal podocytes: protection from injury and molecular effects. Mol Pharmacol 80:389–399
75. Finlin BS, Bodles-Brakhop AM, Yao-Borengasser A, Zhu B, Starnes CP, McGehee RE Jr, Peterson CA, Kern PA, Rasouli N (2012) Regulation of small ubiquitin-like modifier-1, nuclear receptor coreceptor, histone deacetylase 3, and peroxisome proliferator-activated receptor-gamma in human adipose tissue. Metab Syndr Relat Disord 10:312–317
76. Simon M, Grone HJ, Johren O, Kullmer J, Plate KH, Risau W, Fuchs E (1995) Expression of vascular endothelial growth factor and its receptors in human renal ontogenesis and in adult kidney. Am J Physiol 268:F240–50
77. Muller-Deile J, Worthmann K, Saleem M, Tossidou I, Haller H, Schiffer M (2009) The balance of autocrine VEGF-A and VEGF-C determines podocyte survival. Am J Physiol Renal Physiol 297:F1656–67
78. Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH, Quaggin SE (2003) Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111:707–716
79. Wang H, Misaki T, Taupin V, Eguchi A, Ghosh P, Farquhar MG (2014) GIV/Girdin links vascular endothelial growth factor signaling to Akt survival signaling in podocytes independent of nephrin. J Am Soc Nephrol 26:314–327
80. Heydarian M, McCaffrey T, Florea L, Yang Z, Ross MM, Zhou W, Maynard SE (2009) Novel splice variants of sFlt1 are upregulated in preeclampsia. Placenta 30:250–255
81. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658
82. Henao DE, Cadavid AP, Saleem MA (2013) Exogenous vascular endothelial growth factor supplementation can restore the podocyte barrier-forming capacity disrupted by sera of preeclamptic women. J Obstet Gynaecol Res 39:46–52
83. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P (1996) Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. the angiotensin-converting-enzyme inhibition in progressive renal insufficiency study group. N Engl J Med 334:939–945
84. Li Z, Zhang Y, Ying Ma J, Kapoun AM, Shao Q, Kerr I, Lam A, O’Young G, Sannajust F, Stathis P, Schreiner G, Karumanchi SA, Protter AA, Pollitt NS (2007) Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension 50:686–692
85. Veron D, Reidy KJ, Bertuccio C, Teichman J, Villegas G, Jimenez J, Shen W, Kopp JB, Thomas DB, Tufro A (2010) Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int 77:989–999
86. Sung SH, Ziyadeh FN, Wang A, Pyagay PE, Kanwar YS, Chen S (2006) Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice. J Am Soc Nephrol 17:3093–3104
87. de Vriese AS, Tilton RG, Elger M, Stephan CC, Kriz W, Lameire NH (2001) Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol 12:993–1000
88. Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Kopp JB, Kabir MG, Backx PH, Gerber HP, Ferrara N, Barisoni L, Alpers CE, Quaggin SE (2008) VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 358:1129–1136
89. Müller-Deile J, Brocker V, Grunwald V (2010) Renal side effects of VEGF-blocking therapy. NDT Plus 3:172–175
90. Niranjan T, Bielesz B, Gruenwald A, Ponda MP, Kopp JB, Thomas DB, Susztak K (2008) The notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med 14:290–298
91. Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP (1992) CD28-mediated signaling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 356:607–609
92. Walunas TL, Bakker CY, Bluestone JA (1996) CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 183:2541–2550
93. Ishimoto T, Cara-Fuentes G, Wang H, Shimada M, Wasserfall CH, Winter WE, Rivard CJ, Araya CE, Saleem MA, Mathieson PW, Johnson RJ, Garin EH (2013) Serum from minimal change patients in relapse increases CD80 expression in cultured podocytes. Pediatr Nephrol 28:1803–1812
94. Garin EH, Reiser J, Cara-Fuentes G, Wei C, Matar D, Wang H, Alachkar N, Johnson RJ (2014) Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis. Pediatr Nephrol 30:469–477
95. Garin EH, Diaz LN, Mu W, Wasserfall C, Araya C, Segal M, Johnson RJ (2009) Urinary CD80 excretion increases in idiopathic minimal-change disease. J Am Soc Nephrol 20:260–266
96. Yu CC, Fornoni A, Weins A, Hakroush S, Maiguel D, Sageshima J, Chen L, Ciancio G, Faridi MH, Behr D, Campbell KN, Chang JM, Chen HC, Oh J, Faul C, Arnaout MA, Fiorina P, Gupta V, Greka A, 3rd Burke GW, Mundel P (2013) Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 369:2416–2423
97. Benigni A, Gagliardini E, Remuzzi G (2014) Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 370:1261–1263
98. Alachkar N, Carter-Monroe N, Reiser J (2014) Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 370:1263–1264
99. Wei C, Moller CC, Altintas MM, Li J, Schwarz K, Zacchigna S, Xie L, Henger A, Schmid H, Rastaldi MP, Cowan P, Kretzler M, Parrilla R, Bendayan M, Gupta V, Nikolic B, Kalluri R, Carmeliet P, Mundel P, Reiser J (2008) Modification of kidney barrier function by the urokinase receptor. Nat Med 14:55–63
100. Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, Maiguel D, Karumanchi SA, Yap HK, Saleem M, Zhang Q, Nikolic B, Chaudhuri A, Daftarian P, Salido E, Torres A, Salifu M, Sarwal MM, Schaefer F, Morath C, Schwenger V, Zeier M, Gupta V, Roth D, Rastaldi MP, Burke G, Ruiz P, Reiser J (2011) Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 17:952–960
101. Trimarchi H (2013) Primary focal and segmental glomerulosclerosis and soluble factor urokinase-type plasminogen activator receptor. World J Nephrol 2:103–110
102. Trimarchi H, Forrester M, Lombi F, Pomeranz V, Rana MS, Karl A, Andrews J (2014) Amiloride as an alternate adjuvant antiproteinuric agent in fabry disease: the potential roles of plasmin and uPAR. Case Rep Nephrol 2014:854521
103. Maas RJ, Deegens JK, Wetzels JF (2013) Serum suPAR in patients with FSGS: trash or treasure? Pediatr Nephrol 28:1041–1048
104. Cobos E, Jumper C, Lox C (2003) Pretreatment determination of the serum urokinase plasminogen activator and its soluble receptor in advanced small-cell lung cancer or non-small-cell lung cancer. Clin Appl Thromb Hemost 9:241–246
105. Edsfeldt A, Nitulescu M, Grufman H, Gronberg C, Persson A, Nilsson M, Persson M, Bjorkbacka H, Goncalves I (2012) Soluble urokinase plasminogen activator receptor is associated with inflammation in the vulnerable human atherosclerotic plaque. Stroke 43:3305–3312
106. Reiser J, Polu KR, Moller CC, Kenlan P, Altintas MM, Wei C, Faul C, Herbert S, Villegas I, Avila-Casado C, McGee M, Sugimoto H, Brown D, Kalluri R, Mundel P, Smith PL, Clapham DE, Pollak MR (2005) TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 37:739–744
107. Greka A, Mundel P (2011) Balancing calcium signals through TRPC5 and TRPC6 in podocytes. J Am Soc Nephrol 22:1969–1980
108. Krall P, Canales CP, Kairath P, Carmona-Mora P, Molina J, Carpio JD, Ruiz P, Mezzano SA, Li J, Wei C, Reiser J, Young JI, Walz K (2010) Podocyte-specific overexpression of wild type or mutant trpc6 in mice is sufficient to cause glomerular disease. PLoS One 5:e12859
109. Heeringa SF, Moller CC, Du J, Yue L, Hinkes B, Chernin G, Vlangos CN, Hoyer PF, Reiser J, Hildebrandt F (2009) A novel TRPC6 mutation that causes childhood FSGS. PLoS One 4:e7771
110. Hauser PV, Pippin JW, Kaiser C, Krofft RD, Brinkkoetter PT, Hudkins KL, Kerjaschki D, Reiser J, Alpers CE, Shankland SJ (2010) Novel siRNA delivery system to target podocytes in vivo. PLoS One 5:e9463
111. Schiffer M, Bitzer M, Roberts IS, Kopp JB, ten Dijke P, Mundel P, Bottinger EP (2001) Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest 108:807–816
112. Drewe E, McDermott EM, Powell RJ (2000) Treatment of the nephrotic syndrome with etanercept in patients with the tumor necrosis factor receptor-associated periodic syndrome. N Engl J Med 343:1044–1045
113. Akdogan MF, Gucun M, Denizli N, Guney M, Akdag I, Ozcan TB, Duranay M (2011) Complete reversal of nephrotic syndrome secondary to amyloidosis with use of infliximab in a patient with inflammatory bowel disease and ankylosing spondylitis. Ren Fail 33:531–533
114. Gottenberg JE, Merle-Vincent F, Bentaberry F, Allanore Y, Berenbaum F, Fautrel B, Combe B, Durbach A, Sibilia J, Dougados M, Mariette X (2003) Anti-tumor necrosis factor alpha therapy in fifteen patients with AA amyloidosis secondary to inflammatory arthritides: a followup report of tolerability and efficacy. Arthritis Rheum 48:2019–2024
115. Stokes MB, Foster K, Markowitz GS, Ebrahimi F, Hines W, Kaufman D, Moore B, Wolde D, D’Agati VD (2005) Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis. Nephrol Dial Transplant 20:1400–1406
116. Chugh SS, Mace C, Clement LC, Del Nogal AM, Marshall CB (2014) Angiopoietin-like 4 based therapeutics for proteinuria and kidney disease. Front Pharmacol 5:23
117. Niethamer TK, Yardeni T, Leoyklang P, Ciccone C, Astiz-Martinez A, Jacobs K, Dorward HM, Zerfas PM, Gahl WA, Huizing M (2012) Oral monosaccharide therapies to reverse renal and muscle hyposialylation in a mouse model of GNE myopathy. Mol Genet Metab 107:748–755
118. Noh H, King GL (2007) The role of protein kinase C activation in diabetic nephropathy. Kidney Int Suppl 106:S49–53
119. Menne J, Park JK, Boehne M, Elger M, Lindschau C, Kirsch T, Meier M, Gueler F, Fiebeler A, Bahlmann FH, Leitges M, Haller H (2004) Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-alpha-deficient diabetic mice. Diabetes 53:2101–2109
120. Ohshiro Y, Ma RC, Yasuda Y, Hiraoka-Yamamoto J, Clermont AC, Isshiki K, Yagi K, Arikawa E, Kern TS, King GL (2006) Reduction of diabetes-induced oxidative stress, fibrotic cytokine expression, and renal dysfunction in protein kinase Cbeta-null mice. Diabetes 55:3112–3120
121. Tuttle KR, Bakris GL, Toto RD, McGill JB, Hu K, Anderson PW (2005) The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care 28:2686–2690
122. Sahali D, Pawlak A, Le Gouvello S, Lang P, Valanciute A, Remy P, Loirat C, Niaudet P, Bensman A, Guellaen G (2001) Transcriptional and post-transcriptional alterations of IkappaBalpha in active minimal-change nephrotic syndrome. J Am Soc Nephrol 12:1648–1658
123. Coppo R, Camilla R, Porcellini MG, Peruzzi L, Gianoglio B, Amore A, Dapra V, Loiacono E, Fonsato V, Dal Canton A, Esposito C, Esposito P, Tovo PA (2012) Saquinavir in steroid-dependent and -resistant nephrotic syndrome: a pilot study. Nephrol Dial Transplant 27:1902–1910