Podocyte glutamatergic signaling contributes to the function of the glomerular filtration barrier

Laura Giardino, Silvia Armelloni, Alessandro Corbelli, Deborah Mattinzoli, Cristina Zennaro, Dominique Guerrot, Fabien Tourrel, Masami Ikehata, Min Li, Silvia Berra, Michele Carraro, Piergiorgio Messa, Maria P. Rastaldi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1929-1940
Number of pages12
JournalJournal of the American Society of Nephrology
Volume20
Issue number9
DOIs
Publication statusPublished - Sep 2009

ASJC Scopus subject areas

  • Nephrology

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