Nox4 has a crucial role in uric acid-induced oxidative stress and apoptosis in renal tubular cells

Zhu

et al. 2020

IJMS

Hyperuricemia (HUA) is a risk factor for chronic kidney disease (CKD). Serum uric acid (SUA) levels in CKD stage 3–4 patients closely correlate with hyperuricemic nephropathy (HN) morbidity. New uric acid (UA)-lowering strategies are required to prevent CKD. The multiple-purpose connectivity map (CMAP) was used to discover potential molecules against HUA and renal fibrosis. We used HUA and unilateral ureteral occlusion (UUO) model mice to verify renoprotective effects of molecules and explore related mechanisms. In vitro experiments were performed in HepG2 and NRK-52E cells induced by UA. Esculetin was the top scoring compound and lowered serum uric acid (SUA) levels with dual functions on UA excretion. Esculetin exerted these effects by inhibiting expression and activity of xanthine oxidase (XO) in liver, and modulating UA transporters in kidney. The mechanism by which esculetin suppressed XO was related to inhibiting the nuclear translocation of hexokinase 2 (HK2). Esculetin was anti-fibrotic in HUA and UUO mice through inhibiting TGF-β1-activated profibrotic signals. The renoprotection effects of esculetin in HUA mice were associated with lower SUA, alleviation of oxidative stress, and inhibition of fibrosis. Esculetin is a candidate urate-lowering drug with renoprotective activity and the ability to inhibit XO, promote excretion of UA, protect oxidative stress injury, and reduce renal fibrosis.

Section: Discussionmentioning

confidence: 99%

Multiple-Purpose Connectivity Map Analysis Reveals the Benefits of Esculetin to Hyperuricemia and Renal Fibrosis

Zhu

et al. 2020

IJMS

“…It further suggested that Nox4 is the main source of ROS in response to high glucose [31], which may help develop novel effective therapeutic target to target Nox4 for treatment of diabetic nephrology. It was reported that the inhibition of Nox4 prevented uric acid-induced cell injury by suppressing phosphorylation of P38/ERK in HK-2 cells [13]. Thus, P38/ERK activation likely connects Nox4 with HK-2 cell apoptosis upon high glucose stimulations.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the renal source of ROS mostly comes from NADPH oxidase (Nox), and inhibition of Nox by apocynin, a Nox inhibitor, has been proven to protect effectively against diabetic nephropathy [12]. Nox isoform Nox4 is most abundant in the tubule cells and its upregulation indicates renal tubular damage in diabetic nephropathy [13].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of CPU0213, a Dual Endothelin Receptor Antagonist, on Apoptosis via Nox4-Dependent ROS in HK-2 Cells

Shao

et al. 2016

Cell Physiol Biochem

Background/Aims: Our previous studies have indicated that a novel endothelin receptor antagonist CPU0213 effectively normalized renal function in diabetic nephropathy. However, the molecular mechanisms mediating the nephroprotective role of CPU0213 remain unknown. Methods and Results: In the present study, we first detected the role of CPU0213 on apoptosis in human renal tubular epithelial cell (HK-2). It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2 protein in HK-2 cells, which was reversed by CPU0213. The percentage of HK-2 cells that showed Annexin V-FITC binding was markedly suppressed by CPU0213, which confirmed the inhibitory role of CPU0213 on apoptosis. Given the regulation of endothelin (ET) system to oxidative stress, we determined the role of redox signaling in the regulation of CPU0213 on apoptosis. It was demonstrated that the production of superoxide (O₂^-.) was substantially attenuated by CPU0213 treatment in HK-2 cells. We further found that CPU0213 dramatically inhibited expression of Nox4 protein, which gene silencing mimicked the role of CPU0213 on the apoptosis under high glucose stimulation. We finally examined the role of CPU0213 on ET-1 receptors and found that high glucose-induced protein expression of endothelin A and B receptors was dramatically inhibited by CPU0213. Conclusion: Taken together, these results suggest that this Nox4-dependenet O₂^- production is critical for the apoptosis of HK-2 cells in high glucose. Endothelin receptor antagonist CPU0213 has an anti-apoptosis role through Nox4-dependent O₂^-.production, which address the nephroprotective role of CPU0213 in diabetic nephropathy.

“…Potential mechanisms involved in the deleterious metabolic effects of uric acid (UA) include the ability of soluble uric acid to increase oxidative stress, mitochondrial and endoplasmic reticulum dysfunction, endothelial dysfunction, activation of the renin-angiotensin system, as well as increased synthesis and secretion of proinflammatory factors [ 2 – 4 ]. Depending on the cell type, UA may also cause increased proliferation (VSMC) [ 5 , 6 ] or apoptosis (renal tubular cells, endothelial cells) [ 7 , 8 ]. While UA is a prooxidant in the intracellular environment, uric acid may also function as an anti-oxidant and has been proposed to protect the central nervous system in conditions such as Parkinson’s disease [ 9 ]…”

Section: Introductionmentioning

confidence: 99%

Probiotic supplements prevented oxonic acid-induced hyperuricemia and renal damage

et al. 2018

Hyperuricemia is highly prevalent and especially common in subjects with metabolic, cardiovascular and renal diseases. In chronic kidney disease, hyperuricemia is extremely common, and uric acid (UA) excretion relies on gut uricolysis by gut microbiota. Current therapy for lowering serum UA includes drugs that may produce undesired secondary effects. Therefore, this pilot study was designed to evaluate the potential of two probiotic supplements to reduce systemic uric acid concentrations. Secondary objectives were to assess whether the hypouricemic effect related to a therapeutic benefit on the hyperuricemia-induced renal damage and hypertension. Analysis of fecal microbiota was also performed. Groups of 6 rats each were followed for 5 weeks and allocated in the following treatment groups: C = Control; HU-ND = Oxonic acid-induced hyperuricemia (HU) +regular diet; HU-P = HU+placebo; HU-F1 = HU+ probiotics formula 1 and HU-F2 = HU+ probiotics formula 2. We confirmed that oxonic acid-induced hyperuricemia produced hypertension and renal functional and structural changes, along with modest changes in the overall composition of fecal microbiota. Both probiotic-containing diets prevented HU, elevated UA urinary excretion and intrarenal UA accumulation induced by oxonic acid. The hypouricemic effect conferred by probiotic supplementation also prevented the renal changes and hypertension caused by hyperuricemia. However, probiotic treatment did not restore the fecal microbiota. In conclusion, we demonstrated for the first time the ability of probiotics containing uricolytic bacteria to lower serum uric acid in hyperuricemic animals with beneficial consequences on blood pressure and renal disease. As probiotics supplements are innocuous for human health, we recommend clinical studies to test if probiotic supplements could benefit hyperuricemic individuals.