Increased Levels of Renal Lysophosphatidic Acid in Rodent Models with Renal Disease

Hirata, Takashi; Smith, Stanley V.; Takahashi, Teisuke; Miyata, Noriyuki; Roman, Richard J.

doi:10.1124/jpet.120.000353

Cited by 6 publications

(5 citation statements)

References 46 publications

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“…Several studies, including our previous report, have demonstrated that LPA induces the hyperproliferation of mesangial cells [ 7 , 34 – 36 ], and that the pharmacological blockade of LPA/LPAR signaling inhibits renal fibrosis and improves DN in diabetic mice [ 10 , 11 , 37 ]. Consistent with these reports, it has been demonstrated that the levels of LPA are significantly increased in the glomeruli of diabetic mice [ 38 , 39 ] and high-fat diet-induced obese mice [ 40 ]. In addition, a previous study reported that the levels of LPA and precursor lysophosphatidyl choline (LPC) in the urine are significantly higher in diabetic patients with DN than in diabetic patients without DN [ 41 ].…”

Section: Discussionsupporting

confidence: 64%

Inhibition of ChREBP ubiquitination via the ROS/Akt-dependent downregulation of Smurf2 contributes to lysophosphatidic acid-induced fibrosis in renal mesangial cells

Lee

2022

J Biomed Sci

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Background Mesangial cell fibrosis, a typical symptom of diabetic nephropathy (DN), is a major contributor to glomerulosclerosis. We previously reported that the pharmacological blockade of lysophosphatidic acid (LPA) signaling improves DN. Although LPA signaling is implicated in diabetic renal fibrosis, the underlying molecular mechanisms remain unclear. Here, the role of carbohydrate-responsive element-binding protein (ChREBP) in LPA-induced renal fibrosis and the underlying mechanisms were investigated. Methods Eight-week-old wild-type and db/db mice were intraperitoneally injected with the vehicle or an LPAR1/3 antagonist, ki16425 (10 mg/kg), for 8 weeks on a daily basis, following which the mice were sacrificed and renal protein expression was analyzed. SV40 MES13 cells were treated with LPA in the presence or absence of ki16425, and the expression of ChREBP and fibrotic factors, including fibronectin, TGF-β, and IL-1β, was examined. The role of ChREBP in the LPA-induced fibrotic response was investigated by ChREBP overexpression or knockdown. The involvement of Smad ubiquitination regulatory factor-2 (Smurf2), an E3 ligase, in LPA-induced expression of ChREBP and fibrotic factors was investigated by Smurf2 overexpression or knockdown. To identify signaling molecules regulating Smurf2 expression by LPA, pharmacological inhibitors such as A6370 (Akt1/2 kinase inhibitor) and Ly 294002 (PI3K inhibitor) were used. Results The renal expression of ChREBP increased in diabetic db/db mice, and was reduced following treatment with the ki16425. Treatment with LPA induced the expression of ChREBP and fibrotic factors, including fibronectin, TGF-β, and IL-1β, in SV40 MES13 cells, which were positively correlated. The LPA-induced expression of fibrotic factors increased or decreased following ChREBP overexpression and knockdown, respectively. The production of reactive oxygen species (ROS) mediated the LPA-induced expression of ChREBP and fibrotic factors, and LPA decreased Smurf2 expression via Traf4-mediated ubiquitination. The LPA-induced expression of ubiquitinated-ChREBP increased or decreased following Smurf2 overexpression and knockdown, respectively. Additionally, Smurf2 knockdown significantly increased the expression of ChREBP and fibrotic factors. The pharmacological inhibition of Akt signaling suppressed the LPA-induced alterations in the expression of ChREBP and Smurf2. Conclusion Collectively, the results demonstrated that the ROS/Akt-dependent downregulation of Smurf2 and the subsequent increase in ChREBP expression might be one of the mechanisms by which LPA induces mesangial cell fibrosis in DN.

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Section: Discussionsupporting

confidence: 64%

Inhibition of ChREBP ubiquitination via the ROS/Akt-dependent downregulation of Smurf2 contributes to lysophosphatidic acid-induced fibrosis in renal mesangial cells

Lee

2022

J Biomed Sci

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“…Intermediate 65c (200 mg, 0.37 mmol) was reacted according to the general procedure D. The crude residue was purified by flash chromatography on silica-NH cartridge (eluent: cyclohexane/EtOAc from 100/0 to 50/50) and then on a C18 cartridge (eluent: H 2 O/ACN from 100/0 to 50/50) to afford compound 9 (36 mg, 0.068 mmol, 18% yield) as a yellowish solid. LC−MS method 2H),7.76 (dd,J = 8.5,2.2 Hz,1H),1H),7.36 (d,J = 8.0 Hz,1H),4.36 (spt,J = 6.7 Hz,1H),2.94 (tt,J = 11.2,4.0 Hz,1H),2.68 (dd,J = 11.9,6.7 Hz,1H),1H) Synthesis of (S)-N1- (1)(2)(3)sulfonyl)piperidin-4yl)-N2- (7-methylthieno[3,2-d]pyrimidin-4-yl)propane-1,2-diamine (10). Intermediate 65d (244 mg, 0.46 mmol) was reacted according to the general procedure D. The crude residue was purified by flash chromatography on silica-NH cartridge (eluent: cyclohexane/EtOAc from 100/0 to 40/60) to afford compound 10 (63 mg, 0.12 mmol, 26% yield) as a white solid.…”

Section: Synthesis Of N-((2smentioning

confidence: 99%

“…For example, lipid profiling indicates that LPA levels are dramatically higher in bronchoalveolar lavage fluid collected from IPF patients compared to healthy counterparts . LPA levels are also increased in rat following unilateral ureteral obstruction, a preclinical model of renal fibrosis …”

Section: Introductionmentioning

confidence: 99%

“…9 LPA levels are also increased in rat following unilateral ureteral obstruction, a preclinical model of renal fibrosis. 10 The role of LPA 1 receptors in modulating lung fibrotic processes is well established in the clinic. Bristol Myers Squibb (among others) is studying the LPA 1 receptor antagonist BMS-986278 11 in phase 2 clinical trials for IPF and PF-ILD, while BMS-986020, 12 although discontinued in a phase 2 clinical trial in IPF patients for its hepatobiliary toxicity, showed a statistically significant reduction in the change from baseline of forced vital capacity compared to placebo.…”

Section: ■ Introductionmentioning

confidence: 99%

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Discovery of a Potent, Selective, and Orally Bioavailable Tool Compound for Probing the Role of Lysophosphatidic Acid Type 2 Receptor Antagonists in Fibrotic Disorders

et al. 2023

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Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of lung function. Current antifibrotic drugs on the market slow down but do not prevent the progression of the disease and are associated with tolerability issues. The involvement of lysophosphatidic acid receptor 2 (LPA 2 ) in IPF is supported by LPA 2 knockdown studies. To further validate the role of LPA 2 receptors in modulating IPF and potentially other fibrotic processes, a potent and selective LPA 2 receptor antagonist with a good pharmacokinetic (PK) profile is needed. Herein, we report the medicinal chemistry exploration that led to the discovery of a new class of highly potent and selective LPA 2 antagonists. Among them, compound 58 exhibits excellent potency, selectivity, and oral PK profile, making it a suitable tool for probing the involvement of LPA 2 receptors in IPF and other fibrotic processes.

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“…In particular, the LPA-LPAR axis plays an important role in the pathogenesis of kidney disease, lung fibrosis, and cancer [ 16 ]. Indeed, LPA is increased in the serum and kidney cortex of db/db mice, which are used to model type 2 diabetes and obesity [ 17 , 18 ]. Similarly, ATX is increased in the fat and kidney tissues of db/db mice [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of BBT-877, a novel inhibitor of ATX, on a mouse model of type 1 diabetic nephropathy

Lee

Khin

Lee³

et al. 2022

Aging

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Diabetic nephropathy (DN) is one of the common microvascular complications of diabetes. Autotaxin (ATX) is an enzyme with lysophospholipase D activity, producing lysophosphatidic acid (LPA). LPA signaling has been implicated in renal fibrosis, thereby inducing renal dysfunction. BBT-877 is an orally administered small molecule inhibitor of ATX. However, its effect on DN has not been studied so far. In this study, we investigated the effect of BBT-877, a novel inhibitor of ATX, on the pathogenesis of DN in a mouse model of streptozotocin (STZ)-induced diabetes. BBT-877 treatment significantly reduced albuminuria, albumin-to-creatinine ratio (ACR), neutrophil gelatinase-associated lipocalin (NGAL), and glomerular volume compared to the STZ-vehicle group. Interestingly, BBT-877 treatment attenuated hyperglycemia and dyslipidemia in STZ-induced diabetes mice. In the liver, the expression levels of β-oxidation-related genes such as PPAR α and CPT1 were significantly decreased in STZ-induced diabetic mice. However, this effect was reversed by BBT-877 treatment. BBT-877 treatment also suppressed mRNA levels of pro-inflammatory cytokines IL-6, MCP-1, and TNF-α and protein levels of fibrotic factors (TGF-β, fibronectin, CTGF, and collagen type Ι alpha Ι (COL1A1)) in the kidneys of STZ-induced diabetic mice. In conclusion, our results indicate that BBT-877 is effective in preventing the pathogenesis of DN by reducing systemic blood glucose levels and inhibiting inflammation and fibrosis in the renal tissue of diabetes mice. These novel findings suggest that inhibition of ATX may be a potential therapeutic target for DN.

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Increased Levels of Renal Lysophosphatidic Acid in Rodent Models with Renal Disease

Cited by 6 publications

References 46 publications

Inhibition of ChREBP ubiquitination via the ROS/Akt-dependent downregulation of Smurf2 contributes to lysophosphatidic acid-induced fibrosis in renal mesangial cells

Inhibition of ChREBP ubiquitination via the ROS/Akt-dependent downregulation of Smurf2 contributes to lysophosphatidic acid-induced fibrosis in renal mesangial cells

Discovery of a Potent, Selective, and Orally Bioavailable Tool Compound for Probing the Role of Lysophosphatidic Acid Type 2 Receptor Antagonists in Fibrotic Disorders

Effect of BBT-877, a novel inhibitor of ATX, on a mouse model of type 1 diabetic nephropathy

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