Rolle des Sorting-Rezeptors SORLA in der funktionellen Aktivierung von NKCCD2

• Antragsteller: Professor Dr. Thomas E. Willnow
• Fachliche Zuordnung: Nephrologie
• Förderung: Förderung von 2005 bis 2013
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 16133448

• Erstellungsjahr: 2017

Zusammenfassung der Projektergebnisse

Collaborative efforts in this consortium led to the identification of central roles for VPS10P domain receptors in renal ion (SORLA) and water (sortilin) handling. Receptor-mediated sorting of SPAK was identified as the underlying molecular mechanism whereby SORLA modulates NKCC2 action in the kidney, substantiating the relevance of pathways in intracellular protein transport for renal functions. Ongoing work is directed at further clarifying the mode of action of sortilin in renal water handling, an activity that likely involves trafficking of aquaporins in various renal cell types by this sorting receptor.

Projektbezogene Publikationen (Auswahl)

• (2007). Abrogation of Protein Uptake through Megalin-Deficient Proximal Tubules Does Not Safeguard against Tubulointerstitial Injury. J Am Soc Nephrol. 18: 1824-1834
  Theilig, F., Kriz, W., Jerichow, T., Schrade, P., Hahnel, B., Willnow, T., Le Hir, M., and S. Bachmann
  (Siehe online unter https://doi.org/10.1681/ASN.2006111266)
• (2007). Endocytosis provides a major alternative pathway for lysosomal biogenesis. Proc Natl Acad Sci USA 104: 5407-5412
  Nielsen, R., Courtoy, P.J., Jacobsen, C., Dom, G., Lima, W.R., Jadot, M., Willnow, T.E., Devuyst, O., and E.I. Christensen
  (Siehe online unter https://doi.org/10.1073/pnas.0700330104)
• (2008) Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria. Kidney Int 74:1262-9
  Motoyoshi, Y., Matsusaka, T., Saito, A., Pastan, I., Willnow, T.E., Mizutani, S., and I. Ichikawa
  (Siehe online unter https://doi.org/10.1038/ki.2008.405)
• (2008). A novel renal carbonic anhydrase type III plays a role in proximal tubule dysfunction. Kidney Int 74: 52-61
  Gailly, P., Jouret, F., Martin, D., Debaix, H., Parreira, K.S., Nishita, T., Blanchard, A., Antignac, C., Willnow, T.E., Courtoy, P.J., Scheinman, S.J., Christensen, E.I., and O. Devuyst
  (Siehe online unter https://doi.org/10.1038/sj.ki.5002794)
• (2010) Cubilin Is Essential for Albumin Reabsorption in the Renal Proximal Tubule. J Am Soc Nephrol 21: 1859-67
  Amsellem, S., Gburek, J., Hamard, G., Nielsen, R., Willnow, T.E., Devuyst, O., Nexo, E., Verroust, P.J., Christensen, E.I., and R. Kozyraki
  (Siehe online unter https://doi.org/10.1681/ASN.2010050492)
• (2010). SORLA/SORL1 functionally interacts with SPAK to control renal activation of Na+-K+-Clcotransporter 2. Mol Cell Biol 30: 3027-37
  Reiche, R., Theilig, F., Rafiqi, F.H., Militz, D.,Mutig, K., Todiras, M., Christensen, E.I., Ellison, D.H., Bader, M., Nykjaer, A., Bachmann, S., Alessi, D., and T.E. Willnow
  (Siehe online unter https://doi.org/10.1128/MCB.01560-09)
• (2010). Targeted deletion of murine Cldn16 identifies extra- and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting. Am J Physiol: Renal Physiol 298: F1152-F1161
  Will, C., Breiderhoff, T., Thumfart, J., Stuiver, M., Kopplin, K., Sommer, K., Günzel, D., Querfeld, U., Meij, I.C., Shan, Q., Bleich, M., Willnow, T.E., and D. Müller
  (Siehe online unter https://doi.org/10.1152/ajprenal.00499.2009)
• (2011). CNNM2, Encoding a Basolateral Protein Required for Renal Mg(2+) Handling, Is Mutated in Dominant Hypomagnesemia. Am J Hum Genet 88(3): 333-43
  Stuiver, M., Lainez, S., Will, C., Terryn, S., Günzel, D., Debaix, H., Sommer, K., Kopplin, K., Thumfart, J., Kampik, N.B., Querfeld, U., Willnow, T.E., Němec, V., Wagner, C.A., Hoenderop, J.G., Devuyst, O., Knoers, N.V., Bindels, R.J., Meij, I.C., and D. Müller
  (Siehe online unter https://doi.org/10.1016/j.ajhg.2011.02.005)
• (2012). Renal deletion of Claudin-10 impairs paracellular sodium permeability in the thick ascending limb and leads to hypermagnesemia and nephrocalcinosis. Proc Natl Acad Sci USA 109(35): 14241-14246
  Breiderhoff, T., Himmerkus, N., Mutig, K., Stuiver, M., Will, C., Meij, I.C., Bachmann, S., Bleich, M., Willnow, T.E., and D. Müller
  (Siehe online unter https://doi.org/10.1073/pnas.1203834109)
• (2014). Sorting receptor sortilin - a culprit in cardiovascular and neurological diseases. J Mol Med 10.1007/s00109-014-1152-3
  Carlo, A.-S., Nykjaer, A. and T.E. Willnow
  (Siehe online unter https://doi.org/10.1007/s00109-014-1152-3)
• (2016). Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na+-K+-2Cl-Cotransporter. J Am Soc Nephrol 27(1): 107-19
  Borschewski, A., Himmerkus, N., Boldt, C., Blankenstein, K.I., McCormick, J.A., Lazelle, R., Willnow, T.E., Jankowski, V., Plain, A., Bleich, M., Ellison, D.H., Bachman, S. and K. Mutig
  (Siehe online unter https://doi.org/10.1681/ASN.2014070728)