Podocyte glutamatergic signaling contributes to the function of the glomerular filtration barrier.
Podocytes possess the complete machinery for glutamatergic signaling, raising the possibility that neuron-like signaling contributes to glomerular function. To test this, we studied mice and cells lacking Rab3A, a small GTPase that regulates glutamate exocytosis. In addition, we blocked the glutamate ionotropic N-methyl-d-aspartate receptor (NMDAR) with specific antagonists. In mice, the absence of Rab3A and blockade of NMDAR both associated with an increased urinary albumin/creatinine ratio. In humans, NMDAR blockade, obtained by addition of ketamine to general anesthesia, also had an albuminuric effect. In vitro, Rab3A-null podocytes displayed a dysregulated release of glutamate with higher rates of spontaneous exocytosis, explained by a reduction in Rab3A effectors resulting in freedom of vesicles from the actin cytoskeleton. In addition, NMDAR antagonism led to profound cytoskeletal remodeling and redistribution of nephrin in cultured podocytes; the addition of the agonist NMDA reversed these changes. In summary, these results suggest that glutamatergic signaling driven by podocytes contributes to the integrity of the glomerular filtration barrier and that derangements in this signaling may lead to proteinuric renal diseases.
Giardino
Laura
L
Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena and Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy.
Armelloni
Silvia
S
Corbelli
Alessandro
A
Mattinzoli
Deborah
D
Zennaro
Cristina
C
Guerrot
Dominique
D
Tourrel
Fabien
F
Ikehata
Masami
M
Li
Min
M
Berra
Silvia
S
Carraro
Michele
M
Messa
Piergiorgio
P
Rastaldi
Maria P
MP
D000818:Animals; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005089:Exocytosis / Q000502:physiology*; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D007649:Ketamine / Q000031:analogs & derivatives / Q000494:pharmacology; D007674:Kidney Diseases / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020826:rab3A GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C113267:nephrin; D018698:Glutamic Acid; D007649:Ketamine; D016291:Dizocilpine Maleate; D020826:rab3A GTP-Binding Protein; C033419:norketamine