Nephrotic syndrome (NS) is characterized by heavy proteinuria, hypoalbuminemia, and edema. The underlying causes of NS are diverse and are tied to inheritable and environmental factors. A common diagnostic marker for NS is effacement of podocyte foot processes. The formation and maintenance of foot processes are under the control of many signalling molecules including Rho-GTPases. Our knowledge of Rho-GTPases is based largely on the functions of three prototypic members: RhoA, Rac1, and Cdc42. In the event of podocyte injury, the rearrangement to the actin cytoskeleton is orchestrated largely by this family of proteins. The importance of maintaining proper actin dynamics in podocytes has led to much investigation as to how Rho-GTPases and their regulatory molecules form and maintain foot processes as a critical component of the kidney’s filtration barrier. Modern sequencing techniques have allowed for the identification of novel disease causing mutations in genes such as ARHGDIA, encoding Rho-GDIα. Continued use of whole exome sequencing has the potential to lead to the identification of new mutations in genes encoding Rho-GTPases or their regulatory proteins. Expanding our knowledge of the dynamic regulation of the actin network by Rho-GTPases in podocytes will pave the way for effective therapeutic options for NS patients. 1. Introduction The kidneys perform a number of essential functions in vertebrates including hormone secretion [1], blood pressure regulation [2], maintenance of glucose homeostasis [3], and urine formation. The latter process begins at the level of the glomerulus, the most proximal portion of the nephron, the kidney’s functional unit [4]. Reports estimate the number of nephrons per kidney as one million [4, 5]. Our perception of the glomerulus has evolved over time from that of a static structure to a highly dynamic signalling hub that is capable of integrating intracellular cues from its individual structural components [4]. In humans, kidney development begins at five weeks gestation and the full complement of glomeruli is attained by 34 weeks [6]. Individual glomeruli begin development in utero following reciprocal interactions between the ureteric bud and metanephric mesenchyme. Mesenchymal cells are induced to coalesce and undergo a mesenchymal to epithelial transition into structures known as renal vesicles. The renal vesicles undergo a series of morphologic changes, maturing in developmental order to the comma-shape body, S-shape body, precapillary invasion stage, and finally the mature glomerulus [4, 7, 8]. Importantly, the
References
[1]
Y. Sato and M. Yanagita, “Renal anemia: from incurable to curable,” American Journal of Physiology: Renal Physiology, vol. 305, no. 9, pp. F1239–F1248, 2013.
[2]
H. Kobori, M. Nangaku, L. G. Navar, and A. Nishiyama, “The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease,” Pharmacological Reviews, vol. 59, no. 3, pp. 251–287, 2007.
[3]
A. Mather and C. Pollock, “Glucose handling by the kidney,” Kidney international, no. 120, pp. S1–S6, 2011.
[4]
S. E. Quaggin and J. A. Kreidberg, “Development of the renal glomerulus: good neighbors and good fences,” Development, vol. 135, no. 4, pp. 609–620, 2008.
[5]
X. Fulladosa, F. Moreso, J. A. Narváez, J. M. Grinyó, and D. Serón, “Estimation of total glomerular number in stable renal transplants,” Journal of the American Society of Nephrology, vol. 14, no. 10, pp. 2662–2668, 2003.
[6]
N. D. Rosenblum, “Developmental biology of the human kidney,” Seminars in Fetal and Neonatal Medicine, vol. 13, no. 3, pp. 125–132, 2008.
[7]
Y. S. Kanwar, M. L. Jakubowski, L. J. Rosenzweig, and J. T. Gibbons, “De novo cellular synthesis of sulfated proteoglycans of the developing renal glomerulus in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 81, no. 22, pp. 7108–7111, 1984.
[8]
K. J. Reidy and N. D. Rosenblum, “Cell and molecular biology of kidney development,” Seminars in Nephrology, vol. 29, no. 4, pp. 321–337, 2009.
[9]
A. Gatta, A. Verardo, and M. Bolognesi, “Hypoalbuminemia,” Internal and Emergency Medicine, vol. 7, supplement 3, pp. S193–S199, 2012.
[10]
A. Kanfer, “Coagulation factors in nephrotic syndrome,” American Journal of Nephrology, vol. 10, supplement 1, pp. 63–68, 1990.
[11]
H. A. Al-Bander, V. I. Martin, and G. A. Kaysen, “Plasma IgG pool is not defended from urinary loss in nephrotic syndrome,” American Journal of Physiology: Renal Fluid and Electrolyte Physiology, vol. 262, no. 3, pp. F333–F337, 1992.
[12]
B. Haraldsson and M. Jeansson, “Glomerular filtration barrier,” Current Opinion in Nephrology and Hypertension, vol. 18, no. 4, pp. 331–335, 2009.
[13]
J. Reiser, K. R. Polu, C. C. M？ller et al., “TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function,” Nature Genetics, vol. 37, no. 7, pp. 739–744, 2005.
[14]
J. Tao, C. Polumbo, K. Reidy, M. Sweetwyne, and K. Susztak, “A multicolor podocyte reporter highlights heterogeneous podocyte changes in focal segmental glomerulosclerosis,” Kidney International, vol. 85, pp. 972–980, 2014.
[15]
M. C. Menon, P. Y. Chuang, and C. J. He, “The glomerular filtration barrier: components and crosstalk,” International Journal of Nephrology, vol. 2012, Article ID 749010, 9 pages, 2012.
[16]
A. G. Davies, R. J. Postlethwaite, D. A. Price, J. L. Burn, C. A. Houlton, and B. A. Fielding, “Urinary albumin excretion in school children,” Archives of Disease in Childhood, vol. 59, no. 7, pp. 625–630, 1984.
[17]
M. Abbate, C. Zoja, and G. Remuzzi, “How does proteinuria cause progressive renal damage?” Journal of the American Society of Nephrology, vol. 17, no. 11, pp. 2974–2984, 2006.
[18]
M. H. Little, “Regrow or repair: potential regenerative therapies for the kidney,” Journal of the American Society of Nephrology, vol. 17, no. 9, pp. 2390–2401, 2006.
[19]
S. Joshi, R. Andersen, B. Jespersen, and S. Rittig, “Genetics of steroid-resistant nephrotic syndrome: a review of mutation spectrum and suggested approach for genetic testing,” Acta Paediatrica, vol. 102, no. 9, pp. 844–856, 2013.
[20]
N. Hussain, J. A. Zello, J. Vasilevska-Ristovska et al., “The rationale and design of Insight into Nephrotic Syndrome: Investigating Genes, Health and Therapeutics (INSIGHT): a prospective cohort study of childhood nephrotic syndrome,” BMC Nephrology, vol. 14, no. 1, article 25, 2013.
[21]
G. Benoit, E. MacHuca, and C. Antignac, “Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations,” Pediatric Nephrology, vol. 25, no. 9, pp. 1621–1632, 2010.
[22]
H. Y. Gee, P. Saisawat, S. Ashraf et al., “ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling,” The Journal of Clinical Investigation, vol. 123, no. 8, pp. 3243–3253, 2013.
[23]
F. Fakhouri, N. Bocquet, P. Taupin et al., “Steroid-sensitive nephrotic syndrome: from childhood to adulthood,” American Journal of Kidney Diseases, vol. 41, no. 3, pp. 550–557, 2003.
[24]
J. A. Kari and M. Halawani, “Treatment of steroid resistant nephrotic syndrome in children.,” Saudi Journal of Kidney Diseases and Transplantation, vol. 21, no. 3, pp. 484–487, 2010.
[25]
R. M. Lombel, E. M. Hodson, and D. S. Gipson, “Treatment of steroid-resistant nephrotic syndrome in children: new guidelines from KDIGO,” Pediatric Nephrology, vol. 28, no. 3, pp. 409–414, 2013.
[26]
B. G. Hinkes, B. Mucha, C. N. Vlangos et al., “Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2),” Pediatrics, vol. 119, no. 4, pp. e907–e919, 2007.
[27]
H. Jalanko, “Congenital nephrotic syndrome,” Pediatric Nephrology, vol. 24, no. 11, pp. 2121–2128, 2009.
[28]
M. Zenker, T. Aigner, O. Wendler et al., “Human laminin β2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities,” Human Molecular Genetics, vol. 13, no. 21, pp. 2625–2632, 2004.
[29]
B. Hinkes, R. C. Wiggins, R. Gbadegesin et al., “Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible,” Nature Genetics, vol. 38, no. 12, pp. 1397–1405, 2006.
[30]
E. Machuca, G. Benoit, and C. Antignac, “Genetics of nephrotic syndrome: connecting molecular genetics to podocyte physiology,” Human Molecular Genetics, vol. 18, no. 2, pp. R185–R194, 2009.
[31]
A. Greka and P. Mundel, “Cell biology and pathology of podocytes,” Annual Review of Physiology, vol. 74, pp. 299–323, 2012.
[32]
H. Pavenst？dt, W. Kriz, and M. Kretzler, “Cell biology of the glomerular podocyte,” Physiological Reviews, vol. 83, no. 1, pp. 253–307, 2003.
[33]
G. I. Welsh and M. A. Saleem, “The podocyte cytoskeleton-key to a functioning glomerulus in health and disease,” Nature Reviews Nephrology, vol. 8, no. 1, pp. 14–21, 2012.
[34]
T. Benzing, “Signaling at the slit diaphragm,” Journal of the American Society of Nephrology, vol. 15, no. 6, pp. 1382–1391, 2004.
[35]
W. Kriz, I. Shirato, M. Nagata, M. LeHir, and K. V. Lemley, “The podocyte's response to stress: the enigma of foot process effacement,” American Journal of Physiology: Renal Physiology, vol. 304, no. 4, pp. F333–F347, 2013.
[36]
H. Yu, H. Suleiman, A. H. Kim, et al., “Rac1 activation in podocytes induces rapid foot process effacement and proteinuria,” Molecular and Cellular Biology, vol. 33, pp. 4755–4764, 2013.
[37]
R. P. Scott, S. P. Hawley, J. Ruston et al., “Podocyte-specific loss of Cdc42 leads to congenital nephropathy,” Journal of the American Society of Nephrology, vol. 23, no. 7, pp. 1149–1154, 2012.
[38]
S. J. Shankland, “The podocyte's response to injury: role in proteinuria and glomerulosclerosis,” Kidney International, vol. 69, no. 12, pp. 2131–2147, 2006.
[39]
T. Oda, M. Iwasa, T. Aihara, Y. Maeda, and A. Narita, “The nature of the globular- to fibrous-actin transition,” Nature, vol. 457, pp. 441–445, 2009.
[40]
J. Stricker, T. Falzone, and M. L. Gardel, “Mechanics of the F-actin cytoskeleton,” Journal of Biomechanics, vol. 43, no. 1, pp. 9–14, 2010.
[41]
X. Yao and P. A. Rubenstein, “F-actin-like ATPase activity in a polymerization-defective mutant yeast actin (V266G/L267G),” The Journal of Biological Chemistry, vol. 276, no. 27, pp. 25598–25604, 2001.
[42]
J. K. J. Deegens, H. B. P. M. Dijkman, G. F. Borm et al., “Podocyte foot process effacement as a diagnostic tool in focal segmental glomerulosclerosis,” Kidney International, vol. 74, no. 12, pp. 1568–1576, 2008.
[43]
R. C. Nayak, K. H. Chang, N. S. Vaitinadin, and J. A. Cancelas, “Rho GTPases control specific cytoskeleton-dependent functions of hematopoietic stem cells,” Immunological Reviews, vol. 256, pp. 255–268, 2013.
[44]
S. J. Heasman and A. J. Ridley, “Mammalian Rho GTPases: new insights into their functions from in vivo studies,” Nature Reviews Molecular Cell Biology, vol. 9, no. 9, pp. 690–701, 2008.
[45]
E. Boulter, S. Estrach, R. Garcia-Mata, and C. C. Féral, “Off the beaten paths: alternative and crosstalk regulation of Rho GTPases,” FASEB Journal, vol. 26, no. 2, pp. 469–479, 2012.
[46]
S. Pellegrin and H. Mellor, “Actin stress fibers,” Journal of Cell Science, vol. 120, no. 20, pp. 3491–3499, 2007.
[47]
X. R. Bustelo, V. Sauzeau, and I. M. Berenjeno, “GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo,” BioEssays, vol. 29, no. 4, pp. 356–370, 2007.
[48]
M. Amano, M. Nakayama, and K. Kaibuchi, “Rho-kinase/ROCK: a key regulator of the cytoskeleton and cell polarity,” Cytoskeleton, vol. 67, no. 9, pp. 545–554, 2010.
[49]
K. Asanuma, E. Yanagida-Asanuma, C. Faul, Y. Tomino, K. Kim, and P. Mundel, “Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling,” Nature Cell Biology, vol. 8, no. 5, pp. 485–491, 2006.
[50]
K. Asanuma, K. Kim, J. Oh et al., “Synaptopodin regulates the actin-bundling activity of α-actinin in an isoform-specific manner,” The Journal of Clinical Investigation, vol. 115, no. 5, pp. 1188–1198, 2005.
[51]
L. Zhu, R. Jiang, L. Aoudjit, N. Jones, and T. Takano, “Activation of RhoA in podocytes induces focal segmental glomerulosclerosis,” Journal of the American Society of Nephrology, vol. 22, no. 9, pp. 1621–1630, 2011.
[52]
T. Shigehara, C. Zaragoza, C. Kitiyakara et al., “Inducible podocyte-specific gene expression in transgenic mice,” Journal of the American Society of Nephrology, vol. 14, no. 8, pp. 1998–2003, 2003.
[53]
J. Hughes, M. Nangaku, C. E. Alpers, S. J. Shankland, W. G. Couser, and R. J. Johnson, “C5b-9 membrane attack complex mediates endothelial cell apoptosis in experimental glomerulonephritis,” American Journal of Physiology: Renal Physiology, vol. 278, no. 5, pp. F747–F757, 2000.
[54]
H. Zhang, A. V. Cybulsky, L. Aoudjit et al., “Role of Rho-GTPases in complement-mediated glomerular epithelial cell injury,” American Journal of Physiology: Renal Physiology, vol. 293, no. 1, pp. F148–F156, 2007.
[55]
L. Wang, M. J. Ellis, J. A. Gomez et al., “Mechanisms of the proteinuria induced by Rho GTPases,” Kidney International, vol. 81, no. 11, pp. 1075–1085, 2012.
[56]
A. Babelova, F. Jansen, K. Sander, et al., “Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease,” PLoS ONE, vol. 8, no. 11, Article ID e80328, 2013.
[57]
H. Yang, B. Zhao, C. Liao et al., “High glucose-induced apoptosis in cultured podocytes involves TRPC6-dependent calcium entry via the RhoA/ROCK pathway,” Biochemical and Biophysical Research Communications, vol. 434, no. 2, pp. 394–400, 2013.
[58]
K. Matoba, D. Kawanami, R. Okada et al., “Rho-kinase inhibition prevents the progression of diabetic nephropathy by downregulating hypoxia-inducible factor 1α,” Kidney International, vol. 84, no. 3, pp. 545–554, 2013.
[59]
S. Jeruschke, A. K. Büscher, J. Oh et al., “Protective effects of the mTOR inhibitor everolimus on cytoskeletal injury in human podocytes are mediated by RhoA signaling,” PLoS ONE, vol. 8, no. 2, Article ID e55980, 2013.
[60]
L. Zhu, X. Qi, L. Aoudjit et al., “Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes,” American Journal of Physiology: Renal Physiology, vol. 304, no. 7, pp. F849–F862, 2013.
[61]
D. Michaelson, J. Silletti, G. Murphy, P. D'Eustachio, M. Rush, and M. R. Philips, “Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding,” The Journal of Cell Biology, vol. 152, no. 1, pp. 111–126, 2001.
[62]
A. J. Ridley, H. F. Paterson, C. L. Johnston, D. Diekmann, and A. Hall, “The small GTP-binding protein rac regulates growth factor-induced membrane ruffling,” Cell, vol. 70, no. 3, pp. 401–410, 1992.
[63]
M. Venkatareddy, L. Cook, K. Abuarquob, R. Verma, and P. Garg, “Nephrin regulates lamellipodia formation by assembling a protein complex that includes Ship2, Filamin and Lamellipodin,” PLoS ONE, vol. 6, no. 12, Article ID e28710, 2011.
[64]
O. Attias, R. Jiang, L. Aoudjit, H. Kawachi, and T. Takano, “Rac1 contributes to actin organization in glomerular podocytes,” Nephron: Experimental Nephrology, vol. 114, no. 3, pp. e93–e106, 2010.
[65]
J. Zhu, N. Sun, L. Aoudjit et al., “Nephrin mediates actin reorganization via phosphoinositide 3-kinase in podocytes,” Kidney International, vol. 73, no. 5, pp. 556–566, 2008.
[66]
J. V. Small, T. Stradal, E. Vignal, and K. Rottner, “The lamellipodium: where motility begins,” Trends in Cell Biology, vol. 12, no. 3, pp. 112–120, 2002.
[67]
S. Akilesh, H. Suleiman, H. Yu et al., “Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis,” The Journal of Clinical Investigation, vol. 121, no. 10, pp. 4127–4137, 2011.
[68]
R. Verma, I. Kovari, A. Soofi, D. Nihalani, K. Patrie, and L. B. Holzman, “Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization,” The Journal of Clinical Investigation, vol. 116, no. 5, pp. 1346–1359, 2006.
[69]
S. M. Blattner, J. B. Hodgin, M. Nishio et al., “Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury,” Kidney International, vol. 84, pp. 920–930, 2013.
[70]
K. Kojima, A. Davidovits, H. Poczewski et al., “Podocyte flattening and disorder of glomerular basement membrane are associated with splitting of dystroglycan-matrix interaction,” Journal of the American Society of Nephrology, vol. 15, no. 8, pp. 2079–2089, 2004.
[71]
F. Guo, J. A. Cancelas, D. Hildeman, D. A. Williams, and Y. Zheng, “Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development,” Blood, vol. 112, no. 5, pp. 1767–1775, 2008.
[72]
S. Corbetta, S. Gualdoni, G. Ciceri et al., “Essential role of Rac1 and Rac3 GTPases in neuronal development,” FASEB Journal, vol. 23, no. 5, pp. 1347–1357, 2009.
[73]
X. Lin, J. H. Suh, G. Go, and J. H. Miner, “Feasibility of repairing glomerular basement membrane defects in alport syndrome,” Journal of the American Society of Nephrology, vol. 25, no. 4, pp. 687–692, 2014.
[74]
X. Fan, M. Petitt, M. Gamboa et al., “Transient, inducible, placenta-specific gene expression in mice,” Endocrinology, vol. 153, no. 11, pp. 5637–5644, 2012.
[75]
S. Shibata, M. Nagase, S. Yoshida et al., “Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease,” Nature Medicine, vol. 14, no. 12, pp. 1370–1376, 2008.
[76]
I. R. Gupta, C. Baldwin, D. Auguste et al., “ARHGDIA: a novel gene implicated in nephrotic syndrome,” Journal of Medical Genetics, vol. 50, no. 5, pp. 330–338, 2013.
[77]
O. B. Matas, J. á. Martínez-Menárguez, and G. Egea, “Association of Cdc42/N-WASP/Arp2/3 signaling pathway with Golgi membranes,” Traffic, vol. 5, no. 11, pp. 838–846, 2004.
[78]
S. Krugmann, I. Jordens, K. Gevaert, M. Driessens, J. Vandekerckhove, and A. Hall, “Cdc42 induces filopodia by promoting the formation of an IRSp53:Mena complex,” Current Biology, vol. 11, no. 21, pp. 1645–1655, 2001.
[79]
F. Mouawad, H. Tsui, and T. Takano, “Role of Rho-GTPases and their regulatory proteins in glomerular podocyte function,” Canadian Journal of Physiology and Pharmacology, vol. 91, no. 10, pp. 773–782, 2013.
[80]
C. Wei, C. C. M？ller, M. M. Altintas et al., “Modification of kidney barrier function by the urokinase receptor,” Nature Medicine, vol. 14, no. 1, pp. 55–63, 2008.
[81]
R. J. H. Maas, J. K. J. Deegens, and J. F. M. Wetzels, “Serum suPAR in patients with FSGS: trash or treasure?” Pediatric Nephrology, vol. 28, no. 7, pp. 1041–1048, 2013.
[82]
F. C. Luft, “UPAR signaling is under par for the podocyte course,” Journal of Molecular Medicine, vol. 90, no. 12, pp. 1357–1359, 2012.
[83]
M. C. Boonstra, H. W. Verspaget, S. Ganesh et al., “Clinical applications of the urokinase receptor (uPAR) for cancer patients,” Current Pharmaceutical Design, vol. 17, no. 19, pp. 1890–1910, 2011.
[84]
C. Wei, S. El Hindi, J. Li et al., “Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis,” Nature Medicine, vol. 17, no. 8, pp. 952–960, 2011.
[85]
R. Garcia-Mata, E. Boulter, and K. Burridge, “The “invisible hand”: regulation of RHO GTPases by RHOGDIs,” Nature Reviews Molecular Cell Biology, vol. 12, no. 8, pp. 493–504, 2011.
[86]
J. Tcherkezian and N. Lamarche-Vane, “Current knowledge of the large RhoGAP family of proteins,” Biology of the Cell, vol. 99, no. 2, pp. 67–86, 2007.
[87]
K. L. Rossman, C. J. Der, and J. Sondek, “GEF means go: turning on Rho GTPases with guanine nucleotide-exchange factors,” Nature Reviews Molecular Cell Biology, vol. 6, no. 2, pp. 167–180, 2005.
[88]
H. Weavers, S. Prieto-Sánchez, F. Grawe et al., “The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm,” Nature, vol. 457, no. 7227, pp. 322–326, 2009.
[89]
M. Laurin, A. Dumouchel, Y. Fukui, and J. F. Cote, “The Rac-specific exchange factors Dock1 and Dock5 are dispensable for the establishment of the glomerular filtration barrier in vivo,” Small GTPases, vol. 4, no. 4, pp. 221–230, 2013.
[90]
F. Mouawad, L. Aoudjit, R. Jiang, K. Szaszi, and T. Takano, “Role of guanine nucleotide exchange factor-H1 in complement-mediated RhoA activation in glomerular epithelial cells,” The Journal of Biological Chemistry, vol. 289, pp. 4206–4218, 2014.
[91]
J. Birkenfeld, P. Nalbant, B. P. Bohl, O. Pertz, K. M. Hahn, and G. M. Bokoch, “GEF-H1 modulates localized RhoA activation during cytokinesis under the control of mitotic kinases,” Developmental Cell, vol. 12, no. 5, pp. 699–712, 2007.
[92]
K. Tonami, Y. Kurihara, S. Arima et al., “Calpain-6, a microtubule-stabilizing protein, regulates Rac1 activity and cell motility through interaction with GEF-H1,” Journal of Cell Science, vol. 124, no. 8, pp. 1214–1223, 2011.
[93]
A. Togawa, J. Miyoshi, H. Ishizaki et al., “Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIα,” Oncogene, vol. 18, no. 39, pp. 5373–5380, 1999.
[94]
S. T. Hussain, M. Paul, S. Plein et al., “Design and rationale of the MR-INFORM study: stress perfusion cardiovascular magnetic resonance imaging to guide the management of patients with stable coronary artery disease,” Journal of Cardiovascular Magnetic Resonance, vol. 14, no. 1, article 65, 2012.
[95]
L. G. Biesecker, “Exome sequencing makes medical genomics a reality,” Nature Genetics, vol. 42, no. 1, pp. 13–14, 2010.
[96]
S. J. Harvey, G. Jarad, J. Cunningham et al., “Podocyte-specific deletion of dicer alters cytoskeletal dynamics and causes glomerular disease,” Journal of the American Society of Nephrology, vol. 19, no. 11, pp. 2150–2158, 2008.
[97]
S. V. Dandapani, H. Sugimoto, B. D. Matthews et al., “α-actinin-4 is required for normal podocyte adhesion,” The Journal of Biological Chemistry, vol. 282, no. 1, pp. 467–477, 2007.
[98]
N. Shih, J. Li, V. Karpitskii et al., “Congenital nephrotic syndrome in mice lacking CD2-associated protein,” Science, vol. 286, no. 5438, pp. 312–315, 1999.
[99]
M. Barua, E. J. Brown, V. T. Charoonratana, G. Genovese, H. Sun, and M. R. Pollak, “Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis,” Kidney International, vol. 83, no. 2, pp. 316–322, 2013.
[100]
C. Mele, P. Iatropoulos, R. Donadelli et al., “MYO1E mutations and childhood familial focal segmental glomerulosclerosis,” The New England Journal of Medicine, vol. 365, no. 4, pp. 295–306, 2011.
[101]
P. Mundel and J. Reiser, “Proteinuria: an enzymatic disease of the podocyte,” Kidney International, vol. 77, no. 7, pp. 571–580, 2010.
[102]
H. Ma, A. Togawa, K. Soda et al., “Inhibition of podocyte FAK protects against proteinuria and foot process effacement,” Journal of the American Society of Nephrology, vol. 21, no. 7, pp. 1145–1156, 2010.
[103]
R. V. Durvasula and S. J. Shankland, “Podocyte injury and targeting therapy: an update,” Current Opinion in Nephrology and Hypertension, vol. 15, no. 1, pp. 1–7, 2006.
[104]
M. Kestil？, U. Lenkkeri, M. M？nnikk？ et al., “Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome,” Molecular Cell, vol. 1, no. 4, pp. 575–582, 1998.
[105]
W. Bechtel, M. Helmst？dter, J. Balica et al., “Vps34 deficiency reveals the importance of endocytosis for podocyte homeostasis,” Journal of the American Society of Nephrology, vol. 24, no. 5, pp. 727–743, 2013.
[106]
D. P. Leone, K. Srinivasan, C. Brakebusch, and S. K. McConnell, “The Rho GTPase Rac1 is required for proliferation and survival of progenitors in the developing forebrain,” Developmental Neurobiology, vol. 70, no. 9, pp. 659–678, 2010.
[107]
J. Melendez, K. Stengel, X. Zhou et al., “RhoA GTPase is dispensable for actomyosin regulation but is essential for mitosis in primary Mouse embryonic fibroblasts,” The Journal of Biological Chemistry, vol. 286, no. 17, pp. 15132–15137, 2011.
[108]
S. Zhang, X. Zhou, R. A. Lang, and F. Guo, “RhoA of the Rho family small GTPases is essential for B lymphocyte development,” PLoS ONE, vol. 7, no. 3, Article ID e33773, 2012.
[109]
X. Shang, F. Marchioni, C. R. Evelyn et al., “Small-molecule inhibitors targeting G-protein-coupled Rho guanine nucleotide exchange factors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 8, pp. 3155–3160, 2013.
[110]
X. Shang, F. Marchioni, N. Sipes et al., “Rational design of small molecule inhibitors targeting rhoa subfamily Rho GTPases,” Chemistry and Biology, vol. 19, no. 6, pp. 699–710, 2012.
[111]
T. Lu, J. C. He, Z. Wang et al., “HIV-1 Nef disrupts the podocyte actin cytoskeleton by interacting with diaphanous interacting protein,” The Journal of Biological Chemistry, vol. 283, no. 13, pp. 8173–8182, 2008.
