GPRC5b Modulates Inflammatory Response in Glomerular Diseases via NF-κB Pathway

Abstract

BackgroundInflammatory processes play an important role in the pathogenesis of glomerulopathies. Finding novel ways to suppress glomerular inflammation may offer a new way to stop disease progression. However, the molecular mechanisms that initiate and drive inflammation in the glomerulus are still poorly understood.MethodsWe performed large-scale gene expression profiling of glomerulus-associated G protein–coupled receptors (GPCRs) to identify new potential therapeutic targets for glomerulopathies. The expression of Gprc5b in disease was analyzed using quantitative PCR and immunofluorescence, and by analyzing published microarray data sets. In vivo studies were carried out in a podocyte-specific Gprc5b knockout mouse line. Mechanistic studies were performed in cultured human podocytes.ResultsWe identified an orphan GPCR, Gprc5b, as a novel gene highly enriched in podocytes that was significantly upregulated in common human glomerulopathies, including diabetic nephropathy, IgA nephropathy, and lupus nephritis. Similar upregulation of Gprc5b was detected in LPS-induced nephropathy in mice. Studies in podocyte-specific Gprc5b knockout mice showed that Gprc5b was not essential for normal development of the glomerular filtration barrier. However, knockout mice were partially protected from LPS-induced proteinuria and recruitment of inflammatory cells. Mechanistically, RNA sequencing in Gprc5b knockouts mice and experiments in cultured human podocytes showed that Gpr5cb regulated inflammatory response in podocytes via NF-κB signaling.ConclusionsGPRC5b is a novel podocyte-specific receptor that regulates inflammatory response in the glomerulus by modulating the NF-κB signaling pathway. Upregulation of Gprc5b in human glomerulopathies suggests that it may play a role in their pathogenesis.

Orphan G-Protein Coupled Receptor GPRC5B Is Critical for Lymphatic Development

“…GPCR class C group 5 member B (GPRC5B) is an orphan GPCR that belongs to family C of the GPCRs. It is highly expressed in the brain [ 29 , 30 ], adipose tissue [ 31 ] and kidney [ 32 , 33 ]. In an independently generated global knockout mouse line, Gprc5b −/− mice showed behavioral abnormalities [ 26 ], morphological abnormalities in the Purkinje cell axons and disruption of cerebellar synaptic plasticity and motor learning [ 34 ].…”

“…In an independently generated global knockout mouse line, Gprc5b −/− mice showed behavioral abnormalities [ 26 ], morphological abnormalities in the Purkinje cell axons and disruption of cerebellar synaptic plasticity and motor learning [ 34 ]. Additionally, Gprc5b also modulates inflammatory responses in adipocytes [ 31 ], cardiac fibroblasts [ 35 ] and kidney glomeruli [ 33 ]. Consistent with the growth restriction and failure to thrive which we report here, prior studies also showed that loss of Gprc5b protected mice from diet-induced obesity and insulin resistance due to decreased inflammation in white adipose tissue [ 31 ].…”

Immune gene expression and functional networks in distinct lupus nephritis classes

“…We identified 105 significantly differentially expressed genes in class IV LN where all STRING enrichment clusters identified were involved in NF-κB and apoptosis. Accumulating evidence implicates NF-κB in the pathogenesis of LN including podocyte injury, 25 and NF-κB-mediated cytokine expression has been highlighted in non-response. 19 Variants of several genes in TLR/ NF-κB signalling are associated with LN, including TLR 3/7/9, MYD88, IRAK1, TNFAIP3 and TNIP1 , 26 but this is the first time that NF-κB has been attributed to class IV LN.…”

Loss of Rab8a in B cells leads to increased antibody responses and class-switch recombination

“…We found only three DEGs consistently upregulated (GPRC5b) or downregulated (the pseudogenes Gm4864, Gm10036) throughout the different conditions. Of these, GPRC5b, an orphan G-protein-coupled receptor (GPCR) linked to obesity and inflammation, was deemed as an interesting hit ( Hirabayashi & Kim , 2020; Zambrano et al ., 2019). However, this was not further pursued as we could not validate the GPRC5b upregulation at the protein level using western blot ( data not shown ).…”