Serum Autotaxin Levels Are Associated with Proteinuria and Kidney Lesions in Japanese Type 2 Diabetic Patients with Biopsy-proven Diabetic Nephropathy

Shimizu, Miho; Furuichi, Kengo; Toyama, Tadashi; Yamahana, Junya; Ohkawa, Ryunosuke; Igarashi, Koji; Aoki, Junken; Kaneko, Shuichi; Yatomi, Yutaka; Wada, Takashi

doi:10.2169/internalmedicine.55.5473

Cited by 13 publications

(10 citation statements)

References 48 publications

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“…Serum autotaxin levels are associated with proteinuria and kidney lesions in type 2 diabetic patients with biopsy-proven diabetic nephropathy, 13 but the increase in expression of both autotaxin and LPARs in glomerular cells in the diabetic kidney, especially podocytes, suggests a potential role for autocrine and/or paracrine LPAR activation as a mediator of injury. LPA can also transactivate the EGF receptor, 14 and inhibition of EGF receptor activity protects against diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model

Zhang

Wang

Yang

et al. 2017

JASN

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Lysophosphatidic acid (LPA) functions through activation of LPA receptors (LPARs). LPA-LPAR signaling has been implicated in development of fibrosis. However, the role of LPA-LPAR signaling in development of diabetic nephropathy (DN) has not been studied. We examined whether BMS002, a novel dual LPAR1 and LPAR3 antagonist, affects development of DN in endothelial nitric oxide synthase-knockout mice. Treatment of these mice with BMS002 from 8 to 20 weeks of age led to a significant reduction in albuminuria, similar to that observed with renin-angiotensin system inhibition (losartan plus enalapril). LPAR inhibition also prevented the decline in GFR observed in vehicle-treated mice, such that GFR at week 20 differed significantly between vehicle and LPAR inhibitor groups (<0.05). LPAR inhibition also reduced histologic glomerular injury; decreased the expression of profibrotic and fibrotic components, including fibronectin, -smooth muscle actin, connective tissue growth factor, collagen I, and TGF-; and reduced renal macrophage infiltration and oxidative stress. Notably, LPAR inhibition slowed podocyte loss (podocytes per glomerulus ±SEM at 8 weeks: 667±40, =4; at 20 weeks: 364±18 with vehicle,=7, and 536±12 with LPAR inhibition, =7;<0.001 versus vehicle). Finally, LPAR inhibition minimized the production of 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in podocytes and increased the phosphorylation of AKT2, an indicator of AKT2 activity, in kidneys. Thus, the LPAR antagonist BMS002 protects against GFR decline and attenuates development of DN through multiple mechanisms. LPAR antagonism might provide complementary beneficial effects to renin-angiotensin system inhibition to slow progression of DN.

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Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model

Zhang

Wang

Yang

et al. 2017

JASN

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“…In both sample sets, a consensus diagnosis was made by either trained psychologists or psychiatrists according to the DSM-IV-TR(American Psychiatric Association, 2000), on the basis of the Mini-International Neuropsychiatric Interview, Japanese version(Sheehan et al, 1998; Otsubo et al, 2005), additional unstructured interviews, and information from medical histories. Exclusion criteria included a past or current history of other psychiatric disorders such as bipolar disorder, schizoaffective disorder or adjustment disorder, significant neurological illness, or any other significant medical illness, including inflammatory diseases such as liver disease, fibrosis, cancer, kidney disease, arthritis, and Alzheimer’s disease, as these conditions could be due to changes in the ATX/LPA axis(Umemura et al, 2006; Benesch et al, 2016; Shimizu et al, 2016). In Set 1, a total of 6 psychiatric patients displayed co-morbidities, including: 2 with generalized anxiety disorder, 2 with somatization disorder, 1 with panic disorder, and 1 with obsessive-compulsive disorder.…”

Section: Methodsmentioning

confidence: 99%

Reduced Serum and Cerebrospinal Fluid Levels of Autotaxin in Major Depressive Disorder

Itagaki

Takebayashi

Abe

et al. 2019

International Journal of Neuropsychopharmacology

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Background The autotaxin/lysophosphatidic acid axis is involved in diverse biological processes including neurodevelopment, inflammation, and immunological functioning. The lysophosphatidic acid 1 receptor has been implicated in the pathophysiology of major depressive disorder and in the mechanism of action of antidepressants. However, it is unclear whether central or peripheral autotaxin levels are altered in patients with major depressive disorder. Methods Serum autotaxin levels were measured by an enzyme-linked immunosorbent assay in 37 patients with major depressive disorder diagnosed using DSM-IV-TR who underwent electroconvulsive therapy and were compared with those of 47 nondepressed controls matched for age and sex between January 2011 and December 2015. Patient serum levels of autotaxin before and after electroconvulsive therapy were also compared. In a separate sample set, cerebrospinal fluid autotaxin levels were compared between 26 patients with major depressive disorder and 27 nondepressed controls between December 2010 and December 2015. A potential association was examined between autotaxin levels and clinical symptoms assessed with the Hamilton Depression Rating Scale. Results Before electroconvulsive therapy, both serum and cerebrospinal fluidautotaxin levels were significantly lower in major depressive disorder patients than in controls (serum: P = .001, cerebrospinal fluid: P = .038). A significantly negative correlation between serum, but not cerebrospinal fluid, autotaxin levels and depressive symptoms was observed ( P = .032). After electroconvulsive therapy, a parallel increase in serum autotaxin levels and depressive symptoms improvement was observed ( P = .005). Conclusion The current results suggest that serum autotaxin levels are reduced in a state-dependent manner. The reduction of cerebrospinal fluid autotaxin levels suggests a dysfunction in the autotaxin/lysophosphatidic acid axis in the brains of patients with major depressive disorder.

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“…21 Moreover, the expression of autotaxin (ATX), a hydrolysis enzyme that produces LPA from lysophosphatidyl choline, was significantly increased in the kidney cortex of db/ db mice compared with control mice, 22 as well as in the serum of patients with diabetic nephropathy. 23 These observations led us to hypothesize that LPA could be involved in the development of glomerulosclerosis and could contribute to the progression of diabetic nephropathy.…”

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confidence: 99%

Blocking lysophosphatidic acid receptor 1 signaling inhibits diabetic nephropathy in db/db mice

Choi

et al. 2017

Kidney International

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Lysophosphatidic acid (LPA) is known to regulate various biological responses by binding to LPA receptors. The serum level of LPA is elevated in diabetes, but the involvement of LPA in the development of diabetes and its complications remains unknown. Therefore, we studied LPA signaling in diabetic nephropathy and the molecular mechanisms involved. The expression of autotaxin, an LPA synthesis enzyme, and LPA receptor 1 was significantly increased in both mesangial cells (SV40 MES13) maintained in high-glucose media and the kidney cortex of diabetic db/db mice. Increased urinary albumin excretion, increased glomerular tuft area and volume, and mesangial matrix expansion were observed in db/db mice and reduced by treatment with ki16425, a LPA receptor 1/3 antagonist. Transforming growth factor (TGF)β expression and Smad-2/3 phosphorylation were upregulated in SV40 MES13 cells by LPA stimulation or in the kidney cortex of db/db mice, and this was blocked by ki16425 treatment. LPA receptor 1 siRNA treatment inhibited LPA-induced TGFβ expression, whereas cells overexpressing LPA receptor 1 showed enhanced LPA-induced TGFβ expression. LPA treatment of SV40 MES13 cells increased phosphorylated glycogen synthase kinase (GSK)3β at Ser9 and induced translocation of sterol regulatory element-binding protein (SREBP)1 into the nucleus. Blocking GSK3β phosphorylation inhibited SREBP1 activation and consequently blocked LPA-induced TGFβ expression in SV40 MES13 cells. Phosphorylated GSK3β and nuclear SREBP1 accumulation were increased in the kidney cortex of db/db mice and ki16425 treatment blocked these pathways. Thus, LPA receptor 1 signaling increased TGFβ expression via GSK3β phosphorylation and SREBP1 activation, contributing to the development of diabetic nephropathy.

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Serum Autotaxin Levels Are Associated with Proteinuria and Kidney Lesions in Japanese Type 2 Diabetic Patients with Biopsy-proven Diabetic Nephropathy

Cited by 13 publications

References 48 publications

Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model

Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model

Reduced Serum and Cerebrospinal Fluid Levels of Autotaxin in Major Depressive Disorder

Blocking lysophosphatidic acid receptor 1 signaling inhibits diabetic nephropathy in db/db mice

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