Activation of ERK1/2 by NADPH oxidase-originated reactive oxygen species mediates uric acid-induced mesangial cell proliferation

Zhuang, Yibo; Feng, Qi Sheng; Ding, Guofu; Zhao, Min; Che, Ruochen; Bai, Mei; Bao, Hongchu; Zhang, Aihua; Huang, Songming

doi:10.1152/ajprenal.00565.2013

Cited by 32 publications

(25 citation statements)

References 37 publications

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“…Thus the expressions of cyclin D1 and cyclin A2 were chosen as markers for cell cycle progression. Dose-response experiments showed that IS significantly induced cyclin A2 and cyclin D1 expression in MCs consistent with the results which were demonstrated in rat MCs [22]. Similarly, the increase of cell numbers in the S phase was also observed following IS treatment.…”

Section: Discussionsupporting

confidence: 88%

Indoxyl Sulfate Induces Mesangial Cell Proliferation via the Induction of COX-2

Cheng

Sun

et al. 2016

Mediators of Inflammation

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Indoxyl sulfate (IS) is one of important uremic toxins and is markedly accumulated in the circulation of end stage renal disease (ESRD) patients, which might contribute to the damage of residual nephrons and progressive loss of residual renal function (RRF). Thus this study was undertaken to investigate the role of IS in modulating mesangial cell (MC) proliferation and the underlying mechanism. The proliferation of MCs induced by IS was determined by cell number counting, DNA synthase rate, and cell cycle phase analysis. COX-2 expression was examined by Western blotting and qRT-PCR, and a specific COX-2 inhibitor NS398 was applied to define its role in IS-induced MC proliferation. Following IS treatment, MCs exhibited increased total cell number, DNA synthesis rate, and number of cells in S and G2 phases paralleled with the upregulation of cyclin A2 and cyclin D1. Next, we found an inducible inflammation-related enzyme COX-2 was remarkably enhanced by IS, and the inhibition of COX-2 by NS398 significantly blocked IS-induced MC proliferation in line with a blockade of PGE2 production. These findings indicated that IS could induce MC proliferation via a COX-2-mediated mechanism, providing new insights into the understanding and therapies of progressive loss of RRF in ESRD.

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Section: Discussionsupporting

confidence: 88%

Indoxyl Sulfate Induces Mesangial Cell Proliferation via the Induction of COX-2

Cheng

Sun

et al. 2016

Mediators of Inflammation

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“…The higher association between SUA and outcome in the patients with MAP < 90 mm Hg than that in those with MAP ≥90 mm Hg may reflect that hyperuricemia may have more obviously harmful effects on the progression of IgAN in the patients without a higher blood pressure level, which is also a risk factor for the progression of IgAN. Hyperuricemia has been demonstrated to promote mesangial proliferation via NADPH/ reactive oxygen species/ERK1/2 [36], COX-2/mPGES-1/ PGE2 cascade [37,38]; in the present study, this could explain the synergistic effects of hyperuricemia and mesangial proliferation (M1) on the progression of IgAN.…”

Section: Discussionmentioning

confidence: 56%

Uric Acid as a Predictor of Immunoglobulin A Nephropathy Progression: A Cohort Study of 1965 Cases

Zhu

et al. 2018

Am J Nephrol

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Background: The role of serum uric acid (SUA) level in the progression of Immunoglobulin A nephropathy (IgAN) remains controversial. Methods: In a cohort of 1,965 cases with biopsy-proven IgAN, we examined the associations of SUA concentration with the primary outcome of a composite of all-cause mortality or kidney failure (defined as a reduction of estimated glomerular filtration rate [eGFR] by 40% from baseline, requirements for dialysis and transplantation), or the outcome of kidney failure alone, assessed using Cox and logistic regression models, respectively, with adjustment for confounders. Results: At baseline, the mean age was 33.37 ± 11.07 years, eGFR was 101.30 ± 30.49 mL/min/1.73 m², and mean uric acid level was 5.32 ± 1.76 mg/dL. During a median of 7-year follow-up, 317 cases reached the composite outcome of all-cause mortality (5 deaths) or kidney failure (36 cases of dialysis, 5 cases of renal transplantation, and 271 cases with reduction of eGFR by 40% from baseline). After adjustment for demographic and IgAN specific covariates and treatments, a higher quartile of uric acid was linearly associated with an increased risk of the primary outcome (highest versus lowest quartile, hazard ratio [HR] 2.39; 95% CI 1.52–3.75) and kidney failure (highest versus lowest quartile, HR 2.55; 95% CI 1.62–4.01) in the Cox proportional hazards regression models. In the continuous analysis, a 1 mg/dL greater uric acid level was associated with 16% increased risk of primary outcome (HR 1.16, 95% CI 1.07–1.25) and 17% increased risk of kidney failure (HR 1.17, 95% CI 1.08–1.27), respectively, in the fully adjusted model. The multivariate logistic regression analyses for the sensitive analyses drew consistent results. In the subgroup analyses, significant interactions were detected that patients with mean arterial pressure (MAP) < 90 mm Hg or mesangial hypercellularity had a higher association of SUA with the incidence of the primary outcome than those with MAP ≥90 mm Hg or those without mesangial hypercellularity respectively. Hyperuricemia was not significantly associated with the risk of developing the primary outcome in elder patients (≥32 years old), patients with eGFR < 90 mL/min or with tubular atrophy/interstitial fibrosis. Conclusions: SUA level may be positively associated with the progression of IgAN. It was noticeable that the association of hyperuricemia with IgAN progression was less significant in patients with elder age, lower eGFR, or tubular atrophy/interstitial fibrosis, which may be due to some more confounders in association with the IgA progression in these patients. Future prospective studies are warranted to confirm these findings and to investigate the underlying mechanisms.

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“…In VSMC, UA enters the cells via URAT1, resulting in the activation of transcription factors and cytokines, including nuclear factor- κ B, activator protein-1, and monocyte chemoattractant protein-1, ultimately leading to VSMC proliferation and vascular dysfunction [22, 48]. More recent data indicate that UA can induce signaling in renal mesangial cells [50] and collecting duct cells [14]. Thus, it is possible that UA enters into glomerular podocytes, leading to tissue damage and resultant albuminuria in the setting of hyperuricemia.…”

Section: Resultsmentioning

confidence: 99%

Podocyte Injury and Albuminuria in Experimental Hyperuricemic Model Rats

Asakawa

Shibata

Morimoto

et al. 2017

Oxidative Medicine and Cellular Longevity

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Although hyperuricemia is shown to accelerate chronic kidney disease, the mechanisms remain unclear. Accumulating studies also indicate that uric acid has both pro- and antioxidant properties. We postulated that hyperuricemia impairs the function of glomerular podocytes, resulting in albuminuria. Hyperuricemic model was induced by oral administration of 2% oxonic acid, a uricase inhibitor. Oxonic acid caused a twofold increase in serum uric acid levels at 8 weeks when compared to control animals. Hyperuricemia in this model was associated with the increase in blood pressure and the wall-thickening of afferent arterioles as well as arcuate arteries. Notably, hyperuricemic rats showed significant albuminuria, and the podocyte injury marker, desmin, was upregulated in the glomeruli. Conversely, podocin, the key component of podocyte slit diaphragm, was downregulated. Structural analysis using transmission electron microscopy confirmed podocyte injury in this model. We found that urinary 8-hydroxy-2′-deoxyguanosine levels were significantly increased and correlated with albuminuria and podocytopathy. Interestingly, although the superoxide dismutase mimetic, tempol, ameliorated the vascular changes and the hypertension, it failed to reduce albuminuria, suggesting that vascular remodeling and podocyte injury in this model are mediated through different mechanisms. In conclusion, vasculopathy and podocytopathy may distinctly contribute to the kidney injury in a hyperuricemic state.

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Activation of ERK1/2 by NADPH oxidase-originated reactive oxygen species mediates uric acid-induced mesangial cell proliferation

Cited by 32 publications

References 37 publications

Indoxyl Sulfate Induces Mesangial Cell Proliferation via the Induction of COX-2

Indoxyl Sulfate Induces Mesangial Cell Proliferation via the Induction of COX-2

Uric Acid as a Predictor of Immunoglobulin A Nephropathy Progression: A Cohort Study of 1965 Cases

Podocyte Injury and Albuminuria in Experimental Hyperuricemic Model Rats

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