Protective Effect of Tempol on Acute Kidney Injury Through PI3K/Akt/Nrf2 Signaling Pathway

Zhang, Gensheng; Wang, Qiaoling; Zhou, Qin; Wang, Renjun; Xu, Minze; Wang, Huiping; Wang, Lei; Wilcox, Christopher S.; Liu, Ruisheng; Lai, En Yin

doi:10.1159/000443414

Cited by 72 publications

(41 citation statements)

References 45 publications

(58 reference statements)

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“…Previous studies have shown that activation of the Nrf2–Keap1 pathway is a key step in oxidative stress . Activation of Nrf2 plays an important role in antioxidation and anti‐inflammation mechanisms, while ROS are produced in the course of endogenous cellular oxidation.…”

Section: Discussionmentioning

confidence: 99%

Nrf2–Keap1 pathway–mediated effects of resveratrol on oxidative stress and apoptosis in hydrogen peroxide–treated rheumatoid arthritis fibroblast‐like synoviocytes

Zhang

Wang

et al. 2019

Annals of the New York Academy of Sciences

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Resveratrol (Res) is a polyphenolic compound that has a variety of biological functions and activities. This study aimed to explore the mechanisms of the antioxidant and proapoptotic effects of Res in H2O2‐treated rheumatoid arthritis fibroblast‐like synoviocytes (RA‐FLSs) by the Nrf2–Keap1 signaling pathway. We found that 5 µM H2O2 promoted cell proliferation and increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) content in RA‐FLSs. However, Res could reverse these effects in 5 µMH2O2‐treated RA‐FLSs by (1) promoting expression of nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase‐1 (HO‐1), (2) reducing expression of Kelch‐like ECH–related protein 1 (Keap1), (3) inhibiting production of ROS and MDA, (4) blocking activation of nuclear factor‐κB (NF‐κB) p65, (5) inhibiting cell proliferation and migration, and (6) activating Bcl‐2/Bax to induce apoptosis. After lentiviral silencing of Nrf2 (siNrf2) mRNA expression in RA‐FLSs, Res addition did not increase the expression of Nrf2 or HO‐1 to reduce the production of mitochondrial ROS caused by 5 µM H2O2. Res reduced the Bcl‐2/Bax ratio, but siNrf2 reduced the ability of Res to promote apoptosis. We conclude that Res inhibits ROS production by activating the Nrf2 pathway, thereby inhibiting activation of NF‐κB and proliferation and migration of RA‐FLSs, to induce apoptosis. Targeting the Nrf2–Keap1 pathway may be a relevant aim of using Res in the treatment of RA.

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Section: Discussionmentioning

confidence: 99%

Nrf2–Keap1 pathway–mediated effects of resveratrol on oxidative stress and apoptosis in hydrogen peroxide–treated rheumatoid arthritis fibroblast‐like synoviocytes

Zhang

Wang

et al. 2019

Annals of the New York Academy of Sciences

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“…Renal ischemia/reperfusion (I/R) results in considerable alterations in cell function and metabolism and in the structural regularity of the proximal tubule [1-7]. Renal I/R is an important effect of renal dysfunction in renal transplantation, surgical revascularization of the renal artery, partial nephrectomy, and treatment of suprarenal aortic aneurysms [8].…”

Section: Introductionmentioning

confidence: 99%

The Nrf2/HO-1 Pathway Mediates the Antagonist Effect of L-Arginine On Renal Ischemia/Reperfusion Injury in Rats

Tong

Zhou

2017

Kidney Blood Press Res

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Background/Aims: Ischemia/reperfusion (I/R) is the most common cause of acute renal injury. I/R-induced oxidative stress is involved in the development of acute renal injury, which can be reversed by supplementation with L-arginine, a precursor of nitric oxide (NO). This study was conducted to evaluate alterations in the expression of transcription factors [nuclear factor kappa B (NF-κB), nuclear factor-E2-related factor-2 (Nrf2), and heme oxygenase 1 (HO-1)] and heat shock protein 70 (HSP70) in the kidney of I/R-induced injury rats. Methods: Sprague-Dawley (SD) rats were subjected to bilateral renal ischemia for 45 min followed by reperfusion for 24 h. Group 1, Sham; group 2, I/R; group 3, L-arginine; and group 4, L-arginine+zinc protoporphyrin (ZnPP). The levels of serum creatinine (Scr), blood urea nitrogen (BUN), serum nitric oxide (NO), histic malondialdehyde (MDA) and reactive oxygen species (ROS) and superoxide dismutase (SOD) activity were determined, and the expression levels of Nrf2, HO-1, NF-κB, and HSP70 were evaluated. Results: The treatment of rats with L-arginine produced a significant reduction in the levels of BUN, Scr, MDA and a significant enhancement in the level of NO and in the activity of SOD compared to renal I/R groups. The expression levels of Nrf2, HO-1, and HSP70 were strongly increased, and the expression of NF-κB and production of ROS were significantly decreased in the L-arginine group compared to that of the I/R group. ZnPP increased renal damage and displayed effects opposite to those of L-arginine. Conclusion: These findings suggested that L-arginine/NO reduces renal dysfunction associated with I/R of the kidney and may act as a trigger to regulate the NF-κB, HSP70 and Nrf2/HO-1 signaling cascades.

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“…Several mechanisms have been proposed to contribute to the progression of AKI, including increased inflammation [5,6] and oxidative stress [7,8].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Intrarenal Renin-Angiotensin System in Human Acute Tubular Necrosis

Cao

Jin²,

Zhou³

et al. 2016

Kidney Blood Press Res

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Background/Aims: Acute tubular necrosis (ATN), a leading cause of acute kidney injury (AKI), is associated with decreased survival and increased progression of chronic kidney disease. A barrier to improving the clinical outcomes is the incomplete understanding of the pathogenesis of AKI. Our objective is to test the hypothesis that intrarenal renin-angiotensin system (RAS) is overexpressed in patients with ATN and could be an indicator of ATN severity. Methods: A transversal study was conducted in patients with biopsy-proven ATN. Intrarenal expression of angiotensinogen and angiotensin II, and urinary angiotensinogen were measured. Results: Patients with ATN demonstrated upregulation of intrarenal RAS, evidenced by upregulation of intrarenal angiotensinogen and angiotensin II. Patients with ATN also have elevated urinary angiotensinogen level that correlated with the overexpressed intrarenal RAS. Moreover, this increase in intrarenal RAS expression and urinary angiotensinogen was associated with the extent of acute tubular injury and urinary albumin excretion, respectively. Conclusions: We demonstrate that the intrarenal RAS is upregulated in patients with ATN and is associated with the severity of ATN. Urinary angiotensinogen reflects intrarenal RAS status, and is of value to assess the severity of ATN.

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Protective Effect of Tempol on Acute Kidney Injury Through PI3K/Akt/Nrf2 Signaling Pathway

Cited by 72 publications

References 45 publications

Nrf2–Keap1 pathway–mediated effects of resveratrol on oxidative stress and apoptosis in hydrogen peroxide–treated rheumatoid arthritis fibroblast‐like synoviocytes

Nrf2–Keap1 pathway–mediated effects of resveratrol on oxidative stress and apoptosis in hydrogen peroxide–treated rheumatoid arthritis fibroblast‐like synoviocytes

The Nrf2/HO-1 Pathway Mediates the Antagonist Effect of L-Arginine On Renal Ischemia/Reperfusion Injury in Rats

Overexpression of Intrarenal Renin-Angiotensin System in Human Acute Tubular Necrosis

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