title: Functional metabotropic glutamate receptors 1 and 5 are expressed in murine podocytes.
abstract: In non-neuronal cells, glutamate is an extracellular signaling mediator. Since podocytes have glutamate-containing vesicles, we sought to determine glutamate receptor presence and action in glomerular cells. The metabotropic glutamate receptors (mGluR) 1, 5, 6, and 8 were found to be expressed in mouse brain and glomeruli; predominantly in podocytes. In two models of proteinuria (BalB/C mice with puromycin aminonucleoside- and doxorubicin-induced podocyte injury) we found that the selective mGluR1/5 agonist (S)-3,5-dihydroxyphenylglycine (DHPG) attenuated albuminuria and improved the expression of the podocyte marker WT-1. TUNEL staining showed that the number of podocytes undergoing apoptosis was inversely correlated with the number of WT-1-positive cells in glomeruli. When podocytes were treated with DHPG in vitro, they generated cyclic AMP and activated CREB (cyclic AMP response element binding protein). The selective mGluR1/5 antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid, the adenylate cyclase inhibitor SQ22536, and RNA interference knockdown of mGluR1 or mGluR5 all prevented DHPG-induced cAMP generation and CREB activation. DHPG inhibited apoptosis and the decrease of aminonucleoside-induced mitochondrial membrane potential in podocytes but had no effect in the presence of SQ22536 with knockdown mGluR1 or mGluR5. Thus, functional mGluR1 and mGluR5 are expressed in podocytes and their activation protects against albuminuria and podocyte apoptosis, processes that are, at least in part, dependent on cAMP.
authors.affiliation: Renal Division and Molecular Cell Lab for Kidney Disease, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. guleyi2006@yahoo.com.cn
authors.forename: Leyi
authors.initials: L
authors.lastname: Gu
authors.forename: Xinyue
authors.initials: X
authors.lastname: Liang
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Yan
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Ni
authors.forename: Huili
authors.initials: H
authors.lastname: Dai
authors.forename: Jiayuan
authors.initials: J
authors.lastname: Gao
authors.forename: Shan
authors.initials: S
authors.lastname: Mou
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Xinyu
authors.initials: X
authors.lastname: Chen
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Qian
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D011507:Proteinuria / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D011692:Puromycin Aminonucleoside / Q000009:adverse effects / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C578936:Grm5 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; C104077:metabotropic glutamate receptor type 1; D011692:Puromycin Aminonucleoside; C079215:3,5-dihydroxyphenylglycine; D004317:Doxorubicin; D000242:Cyclic AMP; D005998:Glycine