Nck proteins maintain the adult glomerular filtration barrier.
Within the glomerulus, the scaffolding protein nephrin bridges the actin-rich foot processes that extend from adjacent podocytes to form the slit diaphragm. Mutations affecting a number of slit diaphragm proteins, including nephrin, cause glomerular disease through rearrangement of the actin cytoskeleton and disruption of the filtration barrier. We recently established that the Nck family of Src homology 2 (SH2)/SH3 cytoskeletal adaptor proteins can mediate nephrin-dependent actin reorganization. Formation of foot processes requires expression of Nck in developing podocytes, but it is unknown whether Nck maintains podocyte structure and function throughout life. Here, we used an inducible transgenic strategy to delete Nck expression in adult mouse podocytes and found that loss of Nck expression rapidly led to proteinuria, glomerulosclerosis, and altered morphology of foot processes. We also found that podocyte injury reduced phosphorylation of nephrin in adult kidneys. These data suggest that Nck is required to maintain adult podocytes and that phosphotyrosine-based interactions with nephrin may occur in foot processes of resting, mature podocytes.
Jones
Nina
N
Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Road East, New Science Complex, Guelph, Ontario, Canada. jonesmcb@uoguelph.ca
New
Laura A
LA
Fortino
Megan A
MA
Eremina
Vera
V
Ruston
Julie
J
Blasutig
Ivan M
IM
Aoudjit
Lamine
L
Zou
Youling
Y
Liu
Xiuwen
X
Yu
Guo-Liang
GL
Takano
Tomoko
T
Quaggin
Susan E
SE
Pawson
Tony
T
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002460:Cell Line; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000502:physiology*; D005921:Glomerulonephritis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology; D011692:Puromycin Aminonucleoside / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure
D048868:Adaptor Proteins, Signal Transducing; D000900:Anti-Bacterial Agents; D008565:Membrane Proteins; C078332:Nck protein; D015513:Oncogene Proteins; C113267:nephrin; D011692:Puromycin Aminonucleoside; D004318:Doxycycline