Renoprotective effect of the xanthine oxidoreductase inhibitor Topiroxostat under decreased angiotensin II type 1a receptor expression

Ohata, Keiichi; Kamijo‐Ikemori, Atsuko; Sugaya, Takeshi; Hibi, Chihiro; Nakamura, Takashi; Murase, Takayo; Oikawa, Tsuyoshi; Hoshino, Seiko; Katayama, Kimie; Asano, Junko; Kimura, Kenjiro; Shibagaki, Yugo

doi:10.1016/j.ejphar.2017.09.005

Cited by 12 publications

(8 citation statements)

References 41 publications

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“…This interaction is well explained by the observations that uric acid induces the expression of soluble ICAM-1 and proinflammatory cytokines and chemokines in TECs (62,70,162). In accordance with these in vitro findings, macrophage and lymphocyte infiltration was exacerbated by hyperuricemia and lessened by administration of the XO inhibitor in several kidney disease models, including the remnant kidney model (5/6 nephrectomy), diabetic nephropathy, and cyclosporine-and adenine-induced nephropathy (51,62,89,109,123). Cellular communication among tubular and immune cells in the tubulointerstitium plays a pivotal role in the progression of CKD.…”

Section: Tubulointerstitial Inflammation/fibrosissupporting

confidence: 58%

Uric acid and inflammation in kidney disease

Jung

Kim

et al. 2020

American Journal of Physiology-Renal Physiology

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Asymptomatic hyperuricemia is frequently observed in patients with kidney disease. Although a substantial number of epidemiologic studies have suggested that an elevated uric acid level plays a causative role in the development and progression of kidney disease, whether hyperuricemia is simply a result of decreased renal excretion of uric acid or is a contributor to kidney disease remains a matter of debate. Over the last two decades, multiple experimental studies have expanded the knowledge of the biological effects of uric acid beyond its role in gout. In particular, uric acid induces immune system activation and alters the characteristics of resident kidney cells, such as tubular epithelial cells, endothelial cells, and vascular smooth muscle cells, toward a proinflammatory and profibrotic state. These findings have led to an increased awareness of uric acid as a potential and modifiable risk factor in kidney disease. Here, we discuss the effects of uric acid on the immune system and subsequently review the effects of uric acid on the kidneys mainly in the context of inflammation.

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Section: Tubulointerstitial Inflammation/fibrosissupporting

confidence: 58%

Uric acid and inflammation in kidney disease

Jung

Kim

et al. 2020

American Journal of Physiology-Renal Physiology

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“…Western blotting. Protein samples extracted from frozen kidneys (10 μg for HIF-1α, 20 μg for CD34) were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) using NuPAGE 4%-12% Bis-Tris gels and the XCell SureLock Mini-Cell system (Thermo Fisher Scientific, Rockford, IL, USA) 46 . The proteins were separated and transferred to polyvinylidene difluoride membranes, which thereafter were blocked in Blocking One solution (Nacalai Tesque, Kyoto, Japan).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II type 1a receptor loss ameliorates chronic tubulointerstitial damage after renal ischemia reperfusion

Fujita

Ichikawa

Sugaya

et al. 2021

Sci Rep

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We investigate whether suppressing the activation of the angiotensin II type 1a receptor (AT1a) can ameliorate severe chronic tubulointerstitial damage (TID) after renal ischemia reperfusion (IR) using AT1a knockout homozygous (AT1a−/−) male mice. To induce severe chronic TID after renal IR, unilateral renal ischemia was performed via clamping of the right renal pedicle in both AT1a−/− and wild-type (AT1a+/+) mice for 45 min. While marked renal atrophy and severe TID at 70 days postischemia was induced in the AT1a+/+ mice, such a development was not provoked in the AT1a−/− mice. Although the AT1a+/+ mice were administered hydralazine to maintain the same systolic blood pressure (SBP) levels as the AT1a−/− mice with lower SBP levels, hydralazine did not reproduce the renoprotective effects observed in the AT1a−/− mice. Acute tubular injury at 3 days postischemia was similar between the AT1a−/− mice and the AT1a+/+ mice. From our investigations using IR kidneys at 3, 14, and 28 days postischemia, the multiple molecular mechanisms may be related to prevention of severe chronic TID postischemia in the AT1a−/− mice. In conclusion, inactivation of the AT1 receptor may be useful in preventing the transition of acute kidney injury to chronic kidney disease.

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“…XOR activity was measured using the method described previously. 30 In brief, lung homogenate was centrifuged at 105 000 g for 60 minutes at 4 °C. These cytosols were added to a mixture containing ( 15 N 2 )‐xanthine (0.8 mmol/L), NAD + (1 mmol/L), and oxonate (0.013 mmol/L) in 20 mmol/L Tris buffer (pH 8.5), and incubated at 37 °C for 30 minutes.…”

Section: Methodsmentioning

confidence: 99%

Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension

Watanabe

Ishikawa

Abe

et al. 2021

JAHA

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Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

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Renoprotective effect of the xanthine oxidoreductase inhibitor Topiroxostat under decreased angiotensin II type 1a receptor expression

Cited by 12 publications

References 41 publications

Uric acid and inflammation in kidney disease

Uric acid and inflammation in kidney disease

Angiotensin II type 1a receptor loss ameliorates chronic tubulointerstitial damage after renal ischemia reperfusion

Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension

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