Albuminuria and Glomerular Damage in Mice Lacking the Metabotropic Glutamate Receptor 1

Abstract

The metabotropic glutamate (mGlu) receptor 1 (GRM1) has been shown to play an important role in neuronal cells by triggering, through calcium release from intracellular stores, various signaling pathways that finally modulate neuron excitability, synaptic plasticity, and mechanisms of feedback regulation of neurotransmitter release. Herein, we show that Grm1 is expressed in glomerular podocytes and that a glomerular phenotype is exhibited by Grm1 crv4 mice carrying a spontaneous recessive inactivating mutation of the gene. Homozygous Grm1 crv4/crv4 and, to a lesser extent, heterozygous mice show albuminuria, podocyte foot process effacement, and reduced levels of nephrin and other proteins known to contribute to the maintenance of podocyte cell structure. Overall, the present data extend the role of mGlu1 receptor to the glomerular filtration barrier. The regulatory action of mGlu1 receptor in dendritic spine morphology and in the control of glutamate release is well acknowledged in neuronal cells. Analogously, we speculate that mGlu1 receptor may regulate foot process morphology and intercellular signaling in the podocyte. Increasing data provide evidence in favor of the hypothesis that glutamate intercellular signaling in the kidney, mostly driven by podocytes, is relevant to the health of the glomerular filter. Podocytes are highly differentiated cells with a complex ramified structure resembling that of neuronal cells. In common with neurons, podocytes use the same machinery for process formation in such highly arborized structures and possess the necessary vesicular and receptor apparatuses to use glutamatergic transmission.1,2 As recently proved, glutamatergic signaling is relevant to the maintenance of glomerular filter integrity because its dysregulation is accompanied by podocyte alterations and increased albuminuria. Glutamate is known to be the most abundant excitatory neurotransmitter in the central nervous system. Once released into the synaptic cleft from presynaptic terminals, glutamate can bind to glutamate receptors of two categories: the ionotropic glutamate receptors, which are ligand-gated ion channels that mediate fast excitatory neurotransmission, and the G protein-coupled metabotropic glutamate (mGlu) receptors, which mediate slower, modulatory neurotransmission (reviewed by Olive 3 ). Three different types of ionotropic glutamate receptors are located on the postsynaptic dendritic spine: the Nmethyl-D-aspartate (NMDA) receptor, the ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor, and the kainate receptor. The NMDA and AMPA receptors are heterotetrameric protein complexes that regulate the influx of cations (primarily Ca 2ϩ ions) into the neuronal cells. Kainate receptors are tetrameric protein complexes composed of various subunits permeable to Na ϩ and K ϩ ions, and, together with the NMDA and AMPA receptors, they contribute to excitatory postsynaptic currents.

Calcium-Sensing Receptor Stimulation in Cultured Glomerular Podocytes Induces TRPC6-Dependent Calcium Entry and RhoA Activation

“…The heterodimerization of CaSR with group I metabotropic glutamate receptors (mRluR1) in neurons has been established [31]. Interestingly, mRluR1 is also expressed in podocytes and may regulate actin cytoskeleton organization [32, 33]. Our unpublished data suggest that TRPC6 is involved in intracellular calcium signals induced by mRluR activation.…”

Sustained Activation of N-Methyl-d-Aspartate Receptors in Podoctyes Leads to Oxidative Stress, Mobilization of Transient Receptor Potential Canonical 6 Channels, Nuclear Factor of Activated T Cells Activation, and Apoptotic Cell Death

“…The molecular basis for this anomalous feature is not understood, but it suggests that NMDA receptors are not part of the local glutamate signaling pathway recently identified in podocytes (Rastaldi et al, 2006;Giardino et al, 2009). That pathway instead seems to be mediated by metabotropic glutamate receptors (Puliti et al, 2011;Gu et al, 2012). Podocyte (Anderson et al, 2011) and neuronal (Kim et al, 1987;Olney et al, 1987) NMDA receptors are robustly activated by sulfurcontaining derivatives of methionine metabolism, such as L-HCA.…”

“…The most significant is the fact that they cannot be activated by L-glutamate or L-aspartate (Anderson et al, 2011). Thus, although there is evidence that L-glutamate can be locally secreted by podocytes (Giardino et al, 2009), it seems likely that it acts primarily on metabotropic glutamate receptors (Puliti et al, 2011;Gu et al, 2012). However, podocyte NMDA receptors are robustly activated by L-homocysteic acid (L-HCA), an endogenously occurring product of methionine metabolism (Anderson et al, 2011).…”

Expression of Glutamate Receptor Subtype 3 Is Epigenetically Regulated in Podocytes under Diabetic Conditions

“…Glutamatergic signaling through NMDA receptor in podocytes has been reported to contribute to the function of the glomerular filtration barrier [21]. Interestingly, mice lacking the metabotropic glutamate receptor 1 (mGluR1) also developed albuminuria and glomerular damage [20], and selective mGluR1/5 agonist (S)-3,5-dihydroxyphenylglycine (DHPG) attenuated albuminuria and podocyte apoptosis in two proteinuric animal models [32]. The effect of DHPG is thought to be mediated by activation of cyclic AMP and CREB (cyclic AMP response element binding protein), resulting in restoration of mitochondrial function.…”