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Gianesello, Lisa (2017) Protein Uptake at Glomerular Level: Possible Involvement of an Endocytic Machinery in Cell Culture and in Patients with Lupus Nephritis. [Ph.D. thesis]

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Abstract (english)

ClC-5 with megalin (LRP2), cubilin, Disabled 2 (Dab2), and Amnionless (AMN), is part of the molecular complex involved at proximal tubular level in the endocytic re-uptake of low-molecular-weight proteins and albumin. ClC-5, megalin and cubilin expression in podocytes of human renal biopsies was already reported. Moreover, it was demonstrated that podocytes are able to internalize albumin through an endocytic process. It is reasonable to assume that there should be an involvement of this system in protein uptake mediated by podocytes. A disruption of this system can lead to proteinuria which is one of the first manifestation of kidney disease in Systemic Lupus Erythematous (SLE).
Aims of this study were to explore the presence of the tubular endocytic machinery components also in human podocytes in vitro and to evaluate whether albumin modulates this system. Moreover, we wanted to verify and quantify the expression of ClC-5, megalin and cubilin in both glomerular and tubular compartments in renal biopsies of patients presenting Lupus nephritis and observing the presence of a relationship with clinical data.
To verify the presence of an uptake mechanism in human podocytes in vitro, we performed time lapse experiments with a low dose of FITC albumin (10 µg/ml). We observed albumin internalization starting from 2 to 15 hours. To evaluate the uptake kinetic, we stimulated podocytes at different time (30 min and 2 hours) and doses (10 µg/ml, 100 µg/ml and 1 mg/ml) at 37°C and 4°C. We observed a significant dose dependent increase in fluorescence vs controls after 2 hours’ stimulation with a typical receptor-mediated kinetic since it is inhibited at 4 °C. Moreover, we disclosed the presence of ClC-5, Dab2 and AMN beyond megalin and cubilin, in this in vitro system using immunohistochemistry (IHC) and immunofluorescence (IF) techniques, highlighting a co-localization between albumin and both receptors. To analyze whether the proteinuric environment modulates CLCN5, LRP2, CUBN, DAB2 and AMN expression, we stimulated human podocytes with increasing concentrations of BSA (range 10 µg/ml - 30 mg/ml) and we evaluated the mRNA expression at different time points (2, 4, 8, 24, 48 and 72 hours). Using Real Time PCR we observed a significant time and dose dependent increase in CLCN5, CUBN and AMN expression and an up-regulation of DAB2 only at 24 hours.
We collected 23 SLE renal biopsies, 6 control biopsies and 1 case of Minimal Change Disease. As clinical parameters we considered proteinuria and pharmacological therapy. IHC and IF were used to analyze ClC-5, megalin and cubilin protein expression in serial sections. Morphometric quantification revealed a direct correlation between tubular and glomerular expression of all molecules in SLE patients, highlighting a relationship between glomerular and tubular compartments independently from proteinuria levels. Furthermore, preliminary data on patients without ACEi/ARB and immunosuppressive drugs disclosed a positive trend among these molecules at glomerular level.
Interestingly, we revealed megalin and cubilin expression in hypertrophic PECs of some SLE patients and characterization experiments identified a subpopulation with an intermediate phenotype between mature and progenitor cells.
In conclusion, for the first time we demonstrated that human podocytes are naturally committed to perform albumin endocytosis via a receptor-mediated mechanism. Moreover, protein overload upregulates CUBN, AMN and CLCN5 in these cells.
Functional studies regarding the role of cubilin in albumin uptake underlined its participation in this mechanism even if this is not the only pathway involved. Further studies will be necessary to analyze which may be the partner(s) of the CUBAM complex in this mechanism.
For the first time we demonstrated the presence of ClC-5, megalin and cubilin in glomeruli of patients with SLE and MCD in addition to controls confirming in vitro data. Furthermore, in SLE biopsies we highlighted a strong correlation between the two renal compartments in the expression of the protein uptake system, supporting the idea of a partnership between tubular and glomerular cells in albumin uptake via the same mechanism of internalization. In addition, preliminary data on patients without ACEi/ARB and immunosuppressive drugs lead us to suppose that the pharmacological therapy could affect the expression of this system, in particular at glomerular level.
The differences observed from in vivo and in vitro data, especially on megalin expression, underline the involvement of other glomerular cell types in addition to podocytes in protein uptake.
Finally, megalin and cubilin expression in PECs of SLE patients is a real interesting but complex data, since characterization experiments identified a subpopulation with an intermediate phenotype between mature and progenitor cells. Further studies will be performed to better characterize the role of these double-positive cells and their correlation with clinical data and/or disease progression.

Abstract (italian)

ClC-5, megalina (LRP2), cubilina, Disabled 2 (Dab2) ed Amnionless (AMN) fanno parte del complesso molecolare coinvolto a livello del tubulo prossimale nel recupero delle proteine a basso peso molecolare e dell’albumina mediante endocitosi. È già stata riportata la presenza di ClC-5, megalina e cubilina a livello dei podociti in biopsie renali umane. Inoltre è stato dimostrato che i podociti sono in grado di internalizzare l’albumina attraverso un meccanismo di endocitosi. Il mancato funzionamento di questo sistema può portare a proteinuria, che è una delle prime manifestazioni del coinvolgimento renale nel Lupus Eritematoso Sistemico (LES). È quindi ragionevole supporre che vi possa essere un coinvolgimento di questo sistema nel meccanismo di uptake delle proteine da parte dei podociti.
Gli scopi di questo studio sono stati di esplorare la presenza dei componenti del sistema tubulare di endocitosi delle proteine in podociti umani in coltura e di valutare se e come l’albumina ne modulasse l’espressione. Inoltre, si è voluto indagare l’espressione di ClC-5, megalina e cubilina sia a livello glomerulare che tubulare in biopsie renali di pazienti con nefrite lupica, valutando una possibile relazione con i dati clinici.
Abbiamo verificato la presenza di un meccanismo di uptake in podociti umani in coltura attraverso esperimenti di time-lapse con basse dosi di FITC-BSA (10 µg/ml) ed abbiamo osservato l’inizio del processo di internalizzazione in un periodo di tempo variabile dalle 2 alle 15 ore. Per caratterizzare il tipo di cinetica di uptake della FITC-BSA, i podociti sono stati stimolati a differenti tempi (30 min e 2 ore) e dosi (10 µg/ml, 100 µg/ml and 1 mg/ml) mantenendo la coltura a 37°C o 4°C. Si è osservato un aumento significativo della fluorescenza dose-dipendente rispetto al controllo dopo 2 ore dalla stimolazione con una tipica cinetica di internalizzazione recettore-mediata poiché veniva inibita a 4°C. Abbiamo osservato la presenza di ClC-5, Dab2 e AMN oltre a quella di megalina e cubilina in podociti umani in coltura in condizioni basali mediante tecniche di immunoistochimica (IHC) ed immunofluorescenza (IF) ed abbiamo dimostrato la co-localizzazione dei due recettori con l’albumina fluorescente. Per valutare se l’ambiente proteinurico fosse in grado di modulare l’espressione di CLCN5, LRP2, CUBN, DAB2 ed AMN, i podociti umani sono stati stimolati con concentrazioni crescenti di BSA (range 10 µg/ml - 30 mg/ml) e l’espressione dell’RNA messaggero è stata valutata a tempi diversi (2, 4, 8, 24, 48 and 72 hours). Mediante analisi in Real Time PCR, abbiamo osservato un aumento significativo tempo e dose-dipendente di CLCN5, CUBN ed AMN ed un aumento di DAB2 solamente alle 24 ore.
Abbiamo raccolto 23 biopsie renali di pazienti con LES, 6 biopsie di controllo ed un caso di Minimal Change Disease. Come parametri clinici abbiamo considerato la proteinuria e la terapia farmacologica. Mediante IHC ed IF abbiamo analizzato l’espressione proteica di ClC-5, megalina e cubilina in sezioni seriali. La quantificazione eseguita mediante analisi morfometrica ha rivelato una correlazione diretta dell’espressione di tutte le molecole in analisi tra il compartimento tubulare e glomerulare, evidenziando una stretta relazione tra i due compartimenti indipendentemente dai livelli di proteinuria. Inoltre, dati preliminari su pazienti privi di terapia farmacologica (ACEi/ARB o immunosoppressivi) hanno mostrato un trend positivo tra l’espressione di queste molecole a livello glomerulare.
Curiosamente, abbiamo evidenziato l’espressione di megalina e cubilina in cellule parietali della capsula (PECs) con morfologia ipertrofica in alcuni pazienti LES che, mediante esperimenti di caratterizzazione, abbiamo identificato come una nuova sottopopolazione con un fenotipo intermedio tra cellule mature e progenitrici.
Concludendo, per la prima volta abbiamo dimostrato che i podociti umani sono naturalmente predisposti ad effettuare l’endocitosi dell’albumina attraverso un meccanismo recettore-mediato. Inoltre, l’overload proteico è in grado di aumentare l’espressione di CLCN5, CUBN ed AMN in queste cellule.
Studi funzionali per dimostrare il ruolo di cubilina nel processo di uptake dell’albumina hanno sottolineato la sua partecipazione in questo meccanismo anche se, verosimilmente, non è l’unico pathway coinvolto. Ulteriori studi saranno necessari per analizzare quali altre molecole possano essere chiamate in causa in questo meccanismo.
Per la prima volta abbiamo dimostrato la presenza di ClC-5, megalina e cubilina in glomeruli di pazienti con LES, MCD e controlli, confermando i dati in vitro. Inoltre, nelle biopsie dei pazienti LES abbiamo evidenziato una stretta relazione tra i due compartimenti renali nell’espressione dei componenti di questo sistema, supportando l’idea di una partnership tra cellule tubulari e glomerulari nell’uptake dell’albumina attraverso lo stesso meccanismo di internalizzazione. In aggiunta, dati preliminari ottenuti da pazienti privi di terapia con ACEi/ARB o immunosoppressivi ci ha fatto supporre che il trattamento farmacologico possa influire sull’espressione di questo sistema a livello glomerulare. Le differenze osservate tra lo studio in vivo e quello in vitro, in particolare riguardo l’espressione di megalina, suggeriscono il coinvolgimento di altre cellule del glomerulo oltre ai podociti.
Infine, l’espressione di megalina e cubilina nelle PECs dei pazienti LES è un dato molto interessante ma complesso, poiché gli esperimenti di caratterizzazione hanno identificato una sottopopolazione con un fenotipo intermedio tra cellule mature e progenitrici. Ulteriori studi dovranno essere condotti per meglio caratterizzare il ruolo di queste cellule con doppia positività e la loro correlazione con i dati clinici o di progressione della malattia.

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EPrint type:Ph.D. thesis
Tutor:Del Prete, Dorella
Ph.D. course:Ciclo 29 > Corsi 29 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI
Data di deposito della tesi:31 January 2017
Anno di Pubblicazione:31 January 2017
Key Words:ClC-5, Megalin, Cubilin, proteinuria, podocytes, parietal epithelial cells, biopsies
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/14 Nefrologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:10226
Depositato il:03 Nov 2017 10:50
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Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

Agrawal S, Guess AJ, Chanley MA, Smoyer WE. Albumin-induced podocyte injury and protection are associated with regulation of COX-2. Kidney Int. 2014;86:1150-60. Cerca con Google

Aminoff M, Carter JE, Chadwick RB, Johnson C, Gräsbeck R, Abdelaal MA, Broch H, Jenner LB, Verroust PJ, Moestrup SK, de la Chapelle A, Krahe R. Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Nat Genet. 1999;21(3):309-13. Cerca con Google

Amsellem S, Gburek J, Hamard G, Nielsen R, Willnow TE, Devuyst O, Nexo E, Verroust PJ, Christensen EI, Kozyraki R. Cubilin is essential for albumin reabsorption in the renal proximal tubule. J Am Soc Nephrol. 2010;21(11):1859-67. Cerca con Google

Appel D, Kershaw DB, Smeets B, Yuan G, Fuss A, Frye B, Elger M, Kriz W, Floege J, Moeller MJ. Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol. 2009;20(2):333-43. Cerca con Google

Birn H, Fyfe JC, Jacobsen C, Mounier F, Verroust PJ, Orskov H, Willnow TE, Moestrup SK, Christensen EI. Cubilin is an albumin binding protein important for renal tubular albumin reabsorption. J Clin Invest. 2000;105(10):1353-61. Cerca con Google

Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009;55(4):611-22. Cerca con Google

Carson JM, Okamura K, Wakashin H, McFann K, Dobrinskikh E, Kopp JB, Blaine J. Podocytes degrade endocytosed albumin primarily in lysosomes. PLoS One. 2014;9:e99771. Cerca con Google

Ceol M, Tiralongo E, Baelde HJ, Vianello D, Betto G, Marangelli A, Bonfante L, Valente M, Della Barbera M, D'Angelo A, Anglani F, Del Prete D. Involvement of the tubular ClC-type exchanger ClC-5 in glomeruli of human proteinuric nephropathies. PLoS One. 2012;7(9):e45605. Cerca con Google

Chan TM. Treatment of severe lupus nephritis: the new horizon. Nat Rev Nephrol. 2015;11(1):46-61. Cerca con Google

Chang AM, Ohse T, Krofft RD, Wu JS, Eddy AA, Pippin JW, et al. Albumin-induced apoptosis of glomerular parietal epithelial cells is modulated by extracellular signal-regulated kinase 1/2. Nephrol Dial Transplant. 2012;27(4):1330-43. Cerca con Google

Chen S, He FF, Wang H, Fang Z, Shao N, Tian XJ, Liu JS, Zhu ZH, Wang YM, Wang S, Huang K, Zhang C. Calcium entry via TRPC6 mediates albumin overload-induced endoplasmic reticulum stress and apoptosis in podocytes. Cell Calcium. 2011;50(6):523-9. Cerca con Google

Christensen EI. Rapid membrane recycling in renal proximal tubule cells. Eur J Cell Biol. 1982;29(1):43-9. Cerca con Google

Christensen EI, Willnow TE. Essential role of megalin in renal proximal tubule for vitamin homeostasis. J Am Soc Nephrol. 1999;10(10):2224-36. Cerca con Google

Christensen EI, Verroust PJ, Nielsen R. Receptor-mediated endocytosis in renal proximal tubule. Pflugers Arch. 2009;458(6):1039-48. Cerca con Google

Christensen EI, Birn H, Storm T, Weyer K, Nielsen R. Endocytic receptors in the renal proximal tubule. Physiology (Bethesda). 2012;27(4):223-36. Cerca con Google

Christensen EI, Nielsen R, Birn H. From bowel to kidneys: the role of cubilin in physiology and disease. Nephrol Dial Transplant. 2013;28(2):274-81. Cerca con Google

Chung JJ, Huber TB, Godel M, Jarad G, Hartleben B, Kwoh C, Keil A, Karpitskiy A, Hu J, Huh CJ, Cella M, Gross RW, Miner JH, Shaw AS. Albumin-associated free fatty acids induce micropinocytosis in podocytes. J Clin Invest. 2015;125:2307-16. Cerca con Google

Clark WF, Macnab JJ, Sontrop JM, Jain AK, Moist L, Salvadori M, Suri R, Garg AX. Dipstick proteinuria as a screening strategy to identify rapid renal decline. J Am Soc Nephrol. 2011;22(9):1729-36. Cerca con Google

Clement LC, Avila-Casado C, Mace C, Soria E, Bakker WW, Kersten S, Chugh SS. Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med. 2011;17:117-22. Cerca con Google

Coffey S, Costacou T, Orchard T, Erkan E. Akt Links Insulin Signaling to Albumin Endocytosis in Proximal Tubule Epithelial Cells. PLoS One. 2015;10(10):e0140417. Cerca con Google

Copelovitch L, Nash MA, Kaplan BS. Hypothesis: Dent disease is an underrecognized cause of focal glomerulosclerosis. Clin J Am Soc Nephrol. 2007;2:914-8. Cerca con Google

Coudroy G, Gburek J, Kozyraki R, Madsen M, Trugnan G, Moestrup SK, Verroust PJ, Maurice M. Contribution of cubilin and amnionless to processing and membrane targeting of cubilin-amnionless complex. J Am Soc Nephrol. 2005;16(8):2330-7. Cerca con Google

Cramer MT, Charlton JR, Fogo AB, Fathallah-Shaykh SA, Askenazi DJ, Guay-Woodford LM. Expanding the phenotype of proteinuria in Dent disease. A case series. Pediatr Nephrol. 2014;29(10):2051-4. Cerca con Google

Davidson A. What is damaging the kidney in lupus nephritis? Nat Rev Rheumatol. 2016;12(3):143-53. Cerca con Google

De S, Kuwahara S, Saito A. The endocytic receptor megalin and its associated proteins in proximal tubule epithelial cells. Membranes (Basel). 2014;4(3):333-55. Cerca con Google

De Mutiis C, Pasini A, La Scola C, Pugliese F, Montini G. Nephrotic-range Albuminuria as the presenting symptom of Dent-2 disease. Ital J Pediatr. 2015;41:46. Cerca con Google

Devuyst O, Christie PT, Courtoy PJ, Beauwens R, Thakker RV. Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease. Hum Mol Genet. 1999;8:247-57. Cerca con Google

Dobrinskikh E, Okamura K, Kopp JB, Doctor RB, Blaine J. Human podocytes perform polarized, caveolae-dependent albumin endocytosis. Am J Physiol Renal Physiol. 2014;306:F941-51. Cerca con Google

Dobrinskikh E, Lewis L, Brian Doctor R, Okamura K, Lee MG, Altmann C, Faubel S, Kopp JB, Blaine J. Shank2 Regulates Renal Albumin Endocytosis. Physiol Rep. 2015;3(9). pii:e12510. Cerca con Google

Eyre J, Ioannou K, Grubb BD, Saleem MA, Mathieson PW, Brunskill NJ, Christensen EI, Topham PS. Statin-sensitive endocytosis of albumin by glomerular podocytes. Am J Physiol Renal Physiol. 2007;292(2):F674-81. Cerca con Google

Fatima H, Moeller MJ, Smeets B, Yang HC, D'Agati VD, Alpers CE, Fogo AB. Parietal epithelial cell activation marker in early recurrence of FSGS in the transplant. Clin J Am Soc Nephrol. 2012;7(11):1852-8. Cerca con Google

Floege J, Amann K. Primary glomerulonephritides. Lancet. 2016;pii:S0140-6736(16)00272-5. Cerca con Google

Friedrich T, Breiderhoff T, Jentsch TJ. Mutational analysis demonstrates that ClC-4 and ClC-5 directly mediate plasma membrane currents. J Biol Chem. 1999;274:896-902. Cerca con Google

Frishberg Y, Dinour D, Belostotsky R, Becker-Cohen R, Rinat C, Feinstein S, Navon-Elkan P, Ben-Shalom E. Dent's disease manifesting as focal glomerulosclerosis: Is it the tip of the iceberg? Pediatr Nephrol. 2009;24:2369-73. Cerca con Google

Fyfe JC, Ramanujam KS, Ramaswamy K, Patterson DF, Seetharam B. Defective brush-border expression of intrinsic factor-cobalamin receptor in canine inherited intestinal cobalamin malabsorption. J Biol Chem. 1991;266(7):4489-94. Cerca con Google

Fyfe JC, Madsen M, Højrup P, Christensen EI, Tanner SM, de la Chapelle A, He Q, Moestrup SK. The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood. 2004;103(5):1573-9. Cerca con Google

Gianesello L, Ceol M, Priante G, Anglani F, Del Prete D. Proteins lost and found: not only a tubular matter. Jour Clin Nephrol Kidney Dis. In press. Cerca con Google

Grahammer F, Schell C, Huber TB. The podocyte slit diaphragm--from a thin grey line to a complex signalling hub. Nat Rev Nephrol. 2013;9(10):587-98. Cerca con Google

Günther W, Lüchow A, Cluzeaud F, Vandewalle A, Jentsch TJ. ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells. Proc Natl Acad Sci USA. 1998;95:8075-80. Cerca con Google

Hara-Chikuma M, Wang Y, Guggino SE, Guggino WB, Verkman AS. Impaired acidification in early endosomes of ClC-5 deficient proximal tubule. Biochem Biophys Res Commun. 2005;329:941-6. Cerca con Google

Haraldsson B, Nyström J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008;88(2):451-87. Cerca con Google

Hastings RH, Folkesson HG, Matthay MA. Mechanisms of alveolar protein clearance in the intact lung. Am J Physiol Lung Cell Mol Physiol. 2004;286(4):L679-89. Cerca con Google

He F, Chen S, Wang H, Shao N, Tian X, Jiang H, Liu J, Zhu Z, Meng X, Zhang C. Regulation of CD2-associated protein influences podocyte endoplasmic reticulum stress-mediated apoptosis induced by albumin overload. Gene. 2011;484(1-2):18-25. Cerca con Google

Hryciw DH, Ekberg J, Pollock CA, Poronnik P. ClC-5: a chloride channel with multiple roles in renal tubular albumin uptake. Int J Biochem Cell Biol. 2006;38:1036-42. Cerca con Google

Inoue K, Ishibe S. Podocyte endocytosis in the regulation of the glomerular filtration barrier. Am J Physiol Renal Physiol. 2015;309(5):F398-405. Cerca con Google

Jhaveri KD, Fishbane S. Glomerular diseases: entering a new era. Clin J Am Soc Nephrol. 2014;9(3):598-9. Cerca con Google

Jentsch TJ, Günther W, Pusch M, Schwappach B. Properties of voltage-gated chloride channels of the ClC gene family. J Physiol. 1995;482:19S-25. Cerca con Google

Kalantry S, Manning S, Haub O, Tomihara-Newberger C, Lee HG, Fangman J, Disteche CM, Manova K, Lacy E. The amnionless gene, essential for mouse gastrulation, encodes a visceral-endoderm-specific protein with an extracellular cysteine-rich domain. Nat Genet. 2001;27(4):412-6. Cerca con Google

Kaneko K, Hasui M, Hata A, Hata D, Nozu K. Focal segmental glomerulosclerosis in a boy with Dent-2 disease. Pediatr Nephrol. 2010;25(4):781-2. Cerca con Google

Kantarci S, Al-Gazali L, Hill RS, Donnai D, Black GC, Bieth E, Chassaing N, Lacombe D, Devriendt K, Teebi A, Loscertales M, Robson C, Liu T, MacLaughlin DT, Noonan KM, Russell MK, Walsh CA, Donahoe PK, Pober BR. Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nat Genet. 2007;39(8):957-9. Cerca con Google

Kerjaschki, D, Farquhar MG. The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Natl Acad Sci USA. 1982;79:5557-61. Cerca con Google

Kietzmann L, Guhr SS, Meyer TN, Ni L, Sachs M, Panzer U, Stahl RA, Saleem MA, Kerjaschki D, Gebeshuber CA, Meyer-Schwesinger C. MicroRNA-193a Regulates the Transdifferentiation of Human Parietal Epithelial Cells toward a Podocyte Phenotype. J Am Soc Nephrol. 2015;26(6):1389-401. Cerca con Google

Kinugasa S, Tojo A, Sakai T, Tsumura H, Takahashi M, Hirata Y, Fujita T. Selective albuminuria via podocyte albumin transport in puromycin nephrotic rats is attenuated by an inhibitor of NADPH oxidase. Kidney Int. 2011;80:1328-38. Cerca con Google

Koop K, Eikmans M, Wehland M, et al. Selective loss of podoplanin protein expression accompanies proteinuria and precedes alterations in podocyte morphology in a spontaneous proteinuric rat model. Am J Pathol. 2008;173(2):315-26. Cerca con Google

Koral K, Erkan E. PKB/Akt partners with Dab2 in albumin endocytosis. Am J Physiol Renal Physiol. 2012;302(8):F1013-24. Cerca con Google

Kumar V, Abbas AK, Aster JC. Robbins basic pathology. 2013 Canada, Elsevier, 9th ed. Cerca con Google

Kuppe C, Gröne HJ, Ostendorf T, van Kuppevelt TH, Boor P, Floege J, Smeets B, Moeller MJ. Common histological patterns in glomerular epithelial cells in secondary focal segmental glomerulosclerosis. Kidney Int. 2015;88(5):990-8. Cerca con Google

Kur E, Christa A, Veth KN, Gajera CR, Andrade-Navarro MA, Zhang J, Willer JR, Gregg RG, Abdelilah-Seyfried S, Bachmann S, Link BA, Hammes A, Willnow TE. Loss of Lrp2 in zebrafish disrupts pronephric tubular clearance but not forebrain development. Dev Dyn. 2011;240(6):1567-77. Cerca con Google

Kurts C, Panzer U, Anders HJ, Rees AJ. The immune system and kidney disease: basic concepts and clinical implications. Nat Rev Immunol. 2013;13(10):738-53. Cerca con Google

Lasagni L, Romagnani P. Basic research: Podocyte progenitors and ectopic podocytes. Nat Rev Nephrol. 2013;9(12):715-6. Cerca con Google

Lech M, Anders HJ. The pathogenesis of lupus nephritis. J Am Soc Nephrol. 2013;24(9):1357-66. Cerca con Google

Leheste JR, Rolinski B, Vorum H, Hilpert J, Nykjaer A, Jacobsen C, Aucouturier P, Moskaug JO, Otto A, Christensen EI, Willnow TE. Megalin knockout mice as an animal model of low molecular weight proteinuria. Am. J. Pathol. 1999;155:1361-70. Cerca con Google

Leheste JR, Melsen F, Wellner M, Jansen P, Schlichting U, Renner-Müller I, Andreassen TT, Wolf E, Bachmann S, Nykjaer A, Willnow TE. Hypocalcemia and osteopathy in mice with kidney-specific megalin gene defect. FASEB J. 2003;17(2):247-9. Cerca con Google

Liu D, Wen Y, Tang TT, Lv LL, Tang RN, Liu H, Ma KL, Crowley SD, Liu BC. Megalin/Cubulin-Lysosome-mediated Albumin Reabsorption Is Involved in the Tubular Cell Activation of NLRP3 Inflammasome and Tubulointerstitial Inflammation. J Biol Chem. 2015;290(29):18018-28. Cerca con Google

Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P, Rigden SP, Wrong O, Jentsch TJ, Craig IW, Thakker RV. A common molecular basis for three inherited kidney stone diseases. Nature. 1996;379:445-9. Cerca con Google

Luyckx VA, Goda FO, Mount DB, Nishio T, Hall A, Hebert SC, Hammond TG, Yu AS. Intrarenal and subcellular localization of rat CLC5. Am J Physiol. 1998;275:761-9. Cerca con Google

Maunsbach AB. Cellular mechanisms of tubular protein transport. Int Rev Physiol. 1976;11:145-67. Cerca con Google

McMahon GM, Olden M, Garnaas M, Yang Q, Liu X, Hwang SJ, Larson MG; CKDGen Consortium., Goessling W, Fox CS. Sequencing of LRP2 reveals multiple rare variants associated with urinary trefoil factor-3. J Am Soc Nephrol. 2014;25(12):2896-905. Cerca con Google

Morris SM, Cooper JA. Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2. Traffic. 2001;2(2):111-23. Cerca con Google

Nagai M, Meerloo T, Takeda T, Farquhar MG. The adaptor protein ARH escorts megalin to and through endosomes. Mol Biol Cell. 2003;14(12):4984-96. Cerca con Google

Nagai J, Christensen EI, Morris SM, Willnow TE, Cooper JA, Nielsen R. Mutually dependent localization of megalin and Dab2 in the renal proximal tubule. Am J Physiol Renal Physiol. 2005;289(3):F569-76. Cerca con Google

Nielsen R, Christensen EI, Birn H. Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease. Kidney Int. 2016;89(1):58-67. Cerca con Google

Nykjær A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell. 1999;96(4):507-15. Cerca con Google

Nykjær A, Fyfe JC, Kozyraki R, Leheste JR, Jacobsen C, Nielsen MS, Verroust PJ, Aminoff M, de la Chapelle A, Moestrup SK, Ray R, Gliemann J, Willnow TE, Christensen EI. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). Proc Natl Acad Sci U S A. 2001;98(24):13895-900. Cerca con Google

Ohse T, Chang AM, Pippin JW, Jarad G, Hudkins KL, Alpers CE, et al. A new function for parietal epithelial cells: a second glomerular barrier. Am J Physiol Renal Physiol. 2009a;297(6):F1566-74. Cerca con Google

Ohse T, Pippin JW, Chang AM, Krofft RD, Miner JH, Vaughan MR, et al. The enigmatic parietal epithelial cell is finally getting noticed: a review. Kidney Int. 2009b;76(12):1225-38. Cerca con Google

Okamura K, Dummer P, Kopp J, Qiu L, Levi M, Faubel S, Blaine J. Endocytosis of albumin by podocytes elicits an inflammatory response and induces apoptotic cell death. PLoS One. 2013;8:e54817. Cerca con Google

Oliver MH, Harrison NK, Bishop JE, Cole PJ, Laurent GJ. A rapid and convenient assay for counting cells cultured in microwell plates: application for assessment of growth factors. J Cell Sci. 1989;92(Pt 3):513-8. Cerca con Google

Pavenstädt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev. 2003;83(1):253-307. Cerca con Google

Pawluczyk IZ, Pervez A, Ghaderi Najafabadi M, Saleem MA, Topham PS. The effect of albumin on podocytes: the role of the fatty acid moiety and the potential role of CD36 scavenger receptor. Exp Cell Res. 2014;326:251-8. Cerca con Google

Pedersen GA, Chakraborty S, Steinhauser AL, Traub LM, Madsen M. AMN directs endocytosis of the intrinsic factor-vitamin B(12) receptor cubam by engaging ARH or Dab2. Traffic. 2010;11(5):706-20. Cerca con Google

Picollo A, Pusch M. Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Nature. 2005;436:420-3. Cerca con Google

Prabakaran T, Nielsen R, Larsen JV, Sørensen SS, Feldt-Rasmussen U, Saleem MA, Petersen CM, Verroust PJ, Christensen EI. Receptor-mediated endocytosis of α-galactosidase A in human podocytes in Fabry disease. PLoS One. 2011;6(9):e25065. Cerca con Google

Prabakaran T, Christensen EI, Nielsen R, Verroust PJ. Cubilin is expressed in rat and human glomerular podocytes. Nephrol Dial Transplant. 2012;27(8):3156-9. Cerca con Google

Raghavan V, Weisz OA. Flow stimulated endocytosis in the proximal tubule. Curr Opin Nephrol Hypertens. 2015;24(4):359-65. Cerca con Google

Reiser J, Altintas MM. Podocytes. F1000Res. 2016;5. pii: F1000 Faculty Rev-114. Cerca con Google

Ronconi E, Sagrinati C, Angelotti ML, Lazzeri E, Mazzinghi B, Ballerini L, Parente E, Becherucci F, Gacci M, Carini M, Maggi E, Serio M, Vannelli GB, Lasagni L, Romagnani S, Romagnani P. Regeneration of glomerular podocytes by human renal progenitors. J Am Soc Nephrol. 2009;20(2):322-32. Cerca con Google

Sagrinati C, Netti GS, Mazzinghi B, Lazzeri E, Liotta F, Frosali F, Ronconi E, Meini C, Gacci M, Squecco R, Carini M, Gesualdo L, Francini F, Maggi E, Annunziato F, Lasagni L, Serio M, Romagnani S, Romagnani P. Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys. J Am Soc Nephrol. 2006;17(9):2443-56. Cerca con Google

Sahali D, Mulliez N, Chatelet F, Dupuis R, Ronco P, Verroust P. Characterization of a 280-kD protein restricted to the coated pits of the renal brush border and the epithelial cells of the yolk sac. Teratogenic effect of the specific monoclonal antibodies. J Exp Med. 1988;167(1):213-8. Cerca con Google

Saito A, Pietromonaco S, Loo AK, Farquhar MG. Complete cloning and sequencing of rat gp330/“megalin,” a distinctive member of the low density lipoprotein receptor gene family. Proc Natl Acad Sci USA 1994;91:9725-9. Cerca con Google

Saleem MA, O'Hare MJ, Reiser J, Coward RJ, Inward CD, Farren T, Xing CY, Ni L, Mathieson PW, Mundel P. A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression. J Am Soc Nephrol. 2002;13(3):630-8. Cerca con Google

Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000Res. 2016;5. pii: F1000 Faculty Rev-412. Cerca con Google

Sawada H, Stukenbrok H, Kerjaschki D, Farquhar MG. Epithelial polyanion (podocalyxin) is found on the sides but not the soles of the foot processes of the glomerular epithelium. Am J Pathol. 1986;125(2):309-18. Cerca con Google

Scheel O, Zdebik AA, Lourdel S, Jentsch TJ. Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins. Nature. 2005;436:424-7. Cerca con Google

Schießl IM, Hammer A, Kattler V, Gess B, Theilig F, Witzgall R, et al. Intravital Imaging Reveals Angiotensin II-Induced Transcytosis of Albumin by Podocytes. J Am Soc Nephrol. 2016;27(3):731-44. Cerca con Google

Schmid EM, Ford MG, Burtey A, Praefcke GJ, Peak-Chew SY, Mills IG, Benmerah A, McMahon HT. Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly. PLoS Biol 2006;4:e262. Cerca con Google

Schmieder RE, Mann JF, Schumacher H, Gao P, Mancia G, Weber MA, McQueen M, Koon T, Yusuf S; ONTARGET Investigators. Changes in albuminuria predict mortality and morbidity in patients with vascular disease. J Am Soc Nephrol. 2011;22(7):1353-64. Cerca con Google

Scita G, Di Fiore PP. The endocytic matrix. Nature. 2010;463(7280):464-73. Cerca con Google

Seetharam B, Levine JS, Ramasamy M, Alpers DH. Purification, properties, and immunochemical localization of a receptor for intrinsic factor-cobalamin complex in the rat kidney. J Biol Chem. 1988;263(9):4443-9. Cerca con Google

Seetharam B, Christensen EI, Moestrup SK, Hammond TG, Verroust PJ. Identification of rat yolk sac target protein of teratogenic antibodies, gp280, as intrinsic factor-cobalamin receptor. J Clin Invest. 1997;99(10):2317-22. Cerca con Google

Shah M, Baterina OY Jr, Taupin V, Farquhar MG. ARH directs megalin to the endocytic recycling compartment to regulate its proteolysis and gene expression. J Cell Biol. 2013;202(1):113-27. Cerca con Google

Shaheen IS, Finlay E, Prescott K, Russell M, Longoni M, Joss S. Focal segmental glomerulosclerosis in a female patient with Donnai-Barrow syndrome. Clin Dysmorphol. 2010;19(1):35-7. Cerca con Google

Shankland SJ, Smeets B, Pippin JW, Moeller MJ. The emergence of the glomerular parietal epithelial cell. Nat Rev Nephrol. 2014;10(3):158-73. Cerca con Google

Smeets B, Uhlig S, Fuss A, Mooren F, Wetzels JF, Floege J, Moeller MJ. Tracing the origin of glomerular extracapillary lesions from parietal epithelial cells. J Am Soc Nephrol. 2009;20(12):2604-15. Cerca con Google

Smeets B, Kuppe C, Sicking EM, Fuss A, Jirak P, van Kuppevelt TH, Endlich K, Wetzels JF, Gröne HJ, Floege J, Moeller MJ. Parietal epithelial cells participate in the formation of sclerotic lesions in focal segmental glomerulosclerosis. J Am Soc Nephrol. 2011;22(7):1262-74. Cerca con Google

Smeets B, Moeller MJ. Parietal epithelial cells and podocytes in glomerular diseases. Semin Nephrol. 2012;32(4):357-67. Cerca con Google

Smeets B, Stucker F, Wetzels J, Brocheriou I, Ronco P, Gröne HJ, D'Agati V, Fogo AB, van Kuppevelt TH, Fischer HP, Boor P, Floege J, Ostendorf T, Moeller MJ. Detection of activated parietal epithelial cells on the glomerular tuft distinguishes early focal segmental glomerulosclerosis from minimal change disease. Am J Pathol. 2014;184(12):3239-48. Cerca con Google

Smith BT, Mussell JC, Fleming PA, Barth JL, Spyropoulos DD, Cooley MA, Drake CJ, Argraves WS. Targeted disruption of cubilin reveals essential developmental roles in the structure and function of endoderm and in somite formation. BMC Dev Biol. 2006;6:30. Cerca con Google

Soda K, Ishibe S. The function of endocytosis in podocytes. Curr Opin Nephrol Hypertens. 2013;22(4):432-8. Cerca con Google

Storm T, Emma F, Verroust PJ, Hertz JM, Nielsen R, Christensen EI. A patient with cubilin deficiency. N Engl J Med. 2011;364(1):89-91. Cerca con Google

Storm T, Tranebjærg L, Frykholm C, Birn H, Verroust PJ, Nevéus T, Sundelin B, Hertz JM, Holmström G, Ericson K, Christensen EI, Nielsen R. Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration. Nephrol Dial Transplant. 2013a;28(3):585-91. Cerca con Google

Storm T, Zeitz C, Cases O, Amsellem S, Verroust PJ, Madsen M, Benoist JF, Passemard S, Lebon S, Jønsson IM, Emma F, Koldsø H, Hertz JM, Nielsen R, Christensen EI, Kozyraki R. Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome. BMC Med Genet. 2013b;14:111. Cerca con Google

Takeda T, Yamazaki H, Farquhar MG. Identification of an apical sorting determinant in the cytoplasmic tail of megalin. Am J Physiol Cell Physiol. 2003;284(5):C1105-13. Cerca con Google

Tanner SM, Aminoff M, Wright FA, Liyanarachchi S, Kuronen M, Saarinen A, Massika O, Mandel H, Broch H, de la Chapelle A. Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. Nat Genet. 2003;33(3):426-9. Cerca con Google

Taylor MJ, Perrais D, Merrifield CJ. A high precision survey of the molecular dynamics of mammalian clathrin-mediated endocytosis. PLoS Biol. 2011;9(3):e1000604. Cerca con Google

Thakker RV. Chloride channels cough up. Nat Genet. 1997;17:125-7. Cerca con Google

Thakker RV. Pathogenesis of Dent's disease and related syndromes of X linked nephrolithiasis. Kidney Int. 2000;57:787-93. Cerca con Google

Tojo A, Onozato ML, Kitiyakara C, et al. Glomerular albumin filtration through podocyte cell body in puromycin aminonucleoside nephrotic rat. Med Mol Morphol. 2008;41:92-8. Cerca con Google

Vázquez-Carretero MD, Palomo M, García-Miranda P, Sánchez-Aguayo I, Peral MJ, Calonge ML, Ilundain AA. Dab2, megalin, cubilin and amnionless receptor complex might mediate intestinal endocytosis in the suckling rat. J Cell Biochem. 2014;115(3):510-22. Cerca con Google

Vize PD, Woolf AS, Bard JBL. The Kidney from normal development to congenital disease. London, Academic Press, 2003, 1st ed. Cerca con Google

Wahlstedt-Fröberg V, Pettersson T, Aminoff M, Dugué B, Gräsbeck R. Proteinuria in cubilin-deficient patients with selective vitamin B12 malabsorption. Pediatr Nephrol. 2003;18(5):417-21. Cerca con Google

Waldegger S, Jentsch TJ. From tonus to tonicity: physiology of CLC chloride channels. J Am Soc Nephrol. 2000;11:1331-9. Cerca con Google

Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, Looi L-M, Makino H, Moura LA, Nagata M, on behalf of the International Society of Nephrology and Renal Pathology Society Working Group on the Classification of Lupus Nephritis. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15:241-50. Cerca con Google

Weyer K, Storm T, Shan J, Vainio S, Kozyraki R, Verroust PJ, Christensen EI, Nielsen R. Mouse model of proximal tubule endocytic dysfunction. Nephrol Dial Transplant. 2011;26(11):3446-51. Cerca con Google

Wrong OM, Norden AGw, Feest TG. Dent's disease; a familial proximal renal tubular syndrome with hypercalciuria, tubular proteinuria, rickets, nephrocalcinosis and eventual renal failure. Q J Med. 1990;77:1086-7. Cerca con Google

Xu D, Kozyraki R, Newman TC, Fyfe JC. Genetic evidence of an accessory activity required specifically for cubilin brush-border expression and intrinsic factor-cobalamin absorption. Blood. 1999;94(10):3604-6. Cerca con Google

Xu R, Sun S, Huo Y, Yun L, Huang S, Li G, Yan S. Effects of ACEIs Versus ARBs on Proteinuria or Albuminuria in Primary Hypertension: A Meta-Analysis of Randomized Trials. Medicine (Baltimore). 2015;94(39):e1560. Cerca con Google

Yoshida S, Nagase M, Shibata S, Fujita T. Podocyte injury induced by albumin overload in vivo and in vitro: involvement of TGF-beta and p38 MAPK. Nephron Exp Nephrol. 2008;108(3):e57-68. Cerca con Google

Yoshikawa N, Ito H, Akamatsu R, Hazikano H, Okada S, Matsuo T. Glomerular podocyte vacuolation in focal segmental glomerulosclerosis. Arch Pathol Lab Med. 1986;110(5):394-8. Cerca con Google

Zhai XY, Nielsen R, Birn H, Drumm K, Mildenberger S, Freudinger R, Moestrup SK, Verroust PJ, Christensen EI, Gekle M. Cubilin- and megalin-mediated uptake of albumin in cultured proximal tubule cells of opossum kidney. Kidney Int. 2000;58(4):1523-33. Cerca con Google

Zhang Y, George J, Li Y, Olufade R, Zhao X. Matrix metalloproteinase-9 expression is enhanced in renal parietal epithelial cells of zucker diabetic Fatty rats and is induced by albumin in in vitro primary parietal cell culture. PLoS One. 2015;10(4):e0123276. Cerca con Google

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