Lysophosphatidic acid receptor 1 inhibitor, AM095, attenuates diabetic nephropathy in mice by downregulation of TLR4/NF-κB signaling and NADPH oxidase

Lee, Jong Han; Sarker, Mithun Kumer; Choi, Hojung; Shin, Dongyun; Kim, Dong‐Hee; Jun, Hee-Sook

doi:10.1016/j.bbadis.2019.02.001

Cited by 37 publications

(52 citation statements)

References 42 publications

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“…Neuronal apoptosis induced by LPA was accompanied by a decrease in mitochondrial membrane potential (MMP) (Steiner et al, 2000), hence we tested whether mitochondrial dysfunction contributes to LPA-induced cell death. Among the six LPA receptors, LPA1 receptor and LPA2 receptor are most extensively studied and their specific antagonists are widely used in research (Lee et al, 2019;Lopez-Serrano et al, 2019). It has been reported that LPA induces activation of the MAPK pathway, which consists of ERK1/2, p38, and JNK (Park et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic Acid Induces Apoptosis of PC12 Cells Through LPA1 Receptor/LPA2 Receptor/MAPK Signaling Pathway

Zhang

Wang

et al. 2020

Front. Mol. Neurosci.

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Lysophosphatidic acid is a small extracellular signaling molecule, which is elevated in pathological conditions such as ischemic stroke and traumatic brain injury (TBI). LPA regulates the survival of neurons in various diseases. However, the molecular mechanisms underlying LPA-induced neuronal death remain unclear. Here we report that LPA activates LPA1 and LPA2 receptors, and the downstream MAPK pathway to induce the apoptosis of PC12 cells through mitochondrial dysfunction. LPA elicits the activation of ERK1/2, p38, and JNK pathways, decreases the expression of Bcl2, promotes the translocation of Bax, and enhances the activation of caspase-3, resulting in mitochondrial dysfunction and cell apoptosis. This process can be blocked by LPA1 receptor antagonist and LPA2 receptor antagonist and MAPK pathway inhibitors. Our results indicate that LPA1 receptor, LPA2 receptor and MAPK pathway play a critical role in LPA-induced neuronal injury. LPA receptors and MAPK pathways may be novel therapeutic targets for ischemic stroke and TBI, where excessive LPA signaling exist.

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Section: Introductionmentioning

confidence: 99%

Lysophosphatidic Acid Induces Apoptosis of PC12 Cells Through LPA1 Receptor/LPA2 Receptor/MAPK Signaling Pathway

Zhang

Wang

et al. 2020

Front. Mol. Neurosci.

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“…Reduction of NOX3 exerts a protective effect in cochlear injury by reducing the level of oxidative stress (9). On the other hand, LPAR1 inhibitor AM095 treatment inhibits LPA-induced ROS production and NOX expression as well as LPA-induced toll like receptor 4 expression in mesangial cells and in the kidney of streptozotocin-induced diabetic mice (57). In addition, AM095 treatment suppressed LPA-induced pro-in ammatory cytokines through downregulation of phosphorylated NF-κBp65 and c-Jun N-terminal kinases in vitro and in the kidney of streptozotocininduced diabetic mice (57).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, LPAR1 inhibitor AM095 treatment inhibits LPA-induced ROS production and NOX expression as well as LPA-induced toll like receptor 4 expression in mesangial cells and in the kidney of streptozotocin-induced diabetic mice (57). In addition, AM095 treatment suppressed LPA-induced pro-in ammatory cytokines through downregulation of phosphorylated NF-κBp65 and c-Jun N-terminal kinases in vitro and in the kidney of streptozotocininduced diabetic mice (57). LPA signaling through LPAR3 increased expression levels of antioxidant enzymes, consequently inhibiting ROS accumulation and ameliorating cell senescence.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of lysophosphatidic acid receptor 1-3 deteriorates experimental autoimmune encephalomyelitis by inducing oxidative stress

Choi

Lee

et al. 2020

Preprint

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Background Lysophosphatidic acid receptors (LPARs) are G-protein-coupled receptors involved in many physiological functions in the central nervous system. However, the role of the LPARs in multiple sclerosis (MS) has not been clearly defined yet. Methods Here, we investigated the roles of LPARs in myelin oligodendrocyte glycoprotein peptides-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Results Pre-inhibition with antagonists ameliorated behavioral symptoms of EAElo. Specifically, LPAR1-3 antagonist Ki16425 (intraperitoneal) deteriorated symptoms of EAElow associated with increased demyelination, chemokine expression, cellular infiltration, and immune cell activation (microglia and macrophage) in spinal cords of mice compared to the sham group. This LPAR1-3 antagonist also increased the infiltration of CD4+/IFN-γ+ (Th1) and CD4+/IL-17+ (Th17) cells into spinal cords of EAElow mice along with upregulated mRNA expression of IFN-γ and IL-17 and impaired BBB in the spinal cord. The underlying mechanism for negative effects of LPAR1-3 antagonist was associated with the overproduction of reactive oxygen species (ROS)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) 2 and NOX3. Interestingly, LPAR1/2 agonist 1-oleoyl-LPA (LPA 18:1) (intraperitoneal) ameliorated symptoms of EAEhigh and improved representative pathological features of spinal cords of EAEhigh mice. Conclusions Our findings strongly suggest that some agents that can stimulate LPARs might have potential therapeutic implications for autoimmune demyelinating diseases such as MS.

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“…The study found that in a mouse model induced by STZ, AM095 inhibited renal cell inflammatory signaling cascade and reduced renal damage by inhibiting the TLR4/NF-κB and NADPH oxidase systems. The role of LPA1 receptor in the development of diabetic nephropathy was more clearly defined [140].…”

Section: Lpar and Diabetic Nephropathymentioning

confidence: 99%

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

Xiang¹,

Lü²,

Shao³

et al. 2020

J. Cancer

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Lysophosphatidic acid (LPA, 1-acyl-2-hemolytic-sn-glycerol-3-phosphate) extracted from membrane phospholipid is a kind of simple bioactive glycophospholipid, which has many biological functions such as stimulating cell multiplication, cytoskeleton recombination, cell survival, drug-fast, synthesis of DNA and ion transport. Current studies have shown that six G-coupled protein receptors (LPAR1-6) can be activated by LPA. They stimulate a variety of signal transduction pathways through heterotrimeric G-proteins (such as Gα12/13, Gαq/11, Gαi/o and GαS). LPA and its receptors play vital roles in cancers, nervous system diseases, cardiovascular diseases, liver diseases, metabolic diseases, etc. In this article, we discussed the structure of LPA receptors and elucidated their functions in various diseases, in order to better understand them and point out new therapeutic schemes for them.

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Lysophosphatidic acid receptor 1 inhibitor, AM095, attenuates diabetic nephropathy in mice by downregulation of TLR4/NF-κB signaling and NADPH oxidase

Cited by 37 publications

References 42 publications

Lysophosphatidic Acid Induces Apoptosis of PC12 Cells Through LPA1 Receptor/LPA2 Receptor/MAPK Signaling Pathway

Lysophosphatidic Acid Induces Apoptosis of PC12 Cells Through LPA1 Receptor/LPA2 Receptor/MAPK Signaling Pathway

Inhibition of lysophosphatidic acid receptor 1-3 deteriorates experimental autoimmune encephalomyelitis by inducing oxidative stress

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

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