Nox4-SH3YL1 complex is involved in diabetic nephropathy

Lee, Sae Rom; Lee, Hye Eun; Yoo, Jung-Yeon; An, Eun Jung; Song, Soo-Jin; Han, Ki-Hwan; Cha, Dae Ryong; Bae, Yun Soo

doi:10.1016/j.isci.2024.108868

Cited by 3 publications

(2 citation statements)

References 59 publications

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“…Oxidative stress is associated with the activation of pro-fibrotic pathways in the kidney, leading to the deposition of extracellular matrix proteins, tissue remodeling and, ultimately, renal sclerosis in DKD [9,11,15,[62][63][64][65][66][67][68][69][70][71]. In order to examine the effect of EC-NOX5 expression on pathological pathways causing renal injury, this study examined mesangial expansion, glomerulosclerosis, and markers of extracellular matrix genes and proteins, specifically collagen IV and fibronectin.…”

Section: Discussionmentioning

confidence: 99%

Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes

Jandeleit-Dahm,

Kankanamalage,

Dai

et al. 2024

Antioxidants

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Chronic hyperglycemia induces intrarenal oxidative stress due to the excessive production of reactive oxygen species (ROS), leading to a cascade of events that contribute to the development and progression of diabetic kidney disease (DKD). NOX5, a pro-oxidant NADPH oxidase isoform, has been identified as a significant contributor to renal ROS in humans. Elevated levels of renal ROS contribute to endothelial cell dysfunction and associated inflammation, causing increased endothelial permeability, which can disrupt the renal ecosystem, leading to progressive albuminuria and renal fibrosis in DKD. This study specifically examines the contribution of endothelial cell-specific human NOX5 expression in renal pathology in a transgenic mouse model of DKD. This study additionally compares NOX5 with the previously characterized NADPH oxidase, NOX4, in terms of their relative roles in DKD. Regardless of NOX4 pathway, this study found that endothelial cell-specific expression of NOX5 exacerbates renal injury, albuminuria and fibrosis. This is attributed to the activation of the endothelial mesenchymal transition (EMT) pathway via enhanced ROS formation and the modulation of redox-sensitive factors. These findings underscore the potential therapeutic significance of NOX5 inhibition in human DKD. The study proposes that inhibiting NOX5 could be a promising approach for mitigating the progression of DKD and strengthens the case for the development of NOX5-specific inhibitors as a potential therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes

Jandeleit-Dahm,

Kankanamalage,

Dai

et al. 2024

Antioxidants

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“…Previous studies have corroborated our findings, showing an upregulation of NOX4 expression in response to cisplatin, which contributes to oxidative stress [ 35 , 36 ]. This stress, in turn, can activate various inflammatory pathways and lead to fibrotic changes in the kidney, exacerbating initial injury and potentially leading to chronic kidney disease if the injury persists [ 37 , 38 ]. Given its critical role in mediating oxidative stress and subsequent kidney damage, targeting NOX4 has emerged as a promising therapeutic approach [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Trametinib in Alleviating Cisplatin-Induced Acute Kidney Injury: Inhibition of Inflammation, Oxidative Stress, and Tubular Cell Death in a Mouse Model

Lee,

Kim,

Leem

2024

Molecules

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Cisplatin, a platinum-based chemotherapeutic, is effective against various solid tumors, but its use is often limited by its nephrotoxic effects. This study evaluated the protective effects of trametinib, an FDA-approved selective inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), against cisplatin-induced acute kidney injury (AKI) in mice. The experimental design included four groups, control, trametinib, cisplatin, and a combination of cisplatin and trametinib, each consisting of eight mice. Cisplatin was administered intraperitoneally at a dose of 20 mg/kg to induce kidney injury, while trametinib was administered via oral gavage at 3 mg/kg daily for three days. Assessments were conducted 72 h after cisplatin administration. Our results demonstrate that trametinib significantly reduces the phosphorylation of MEK1/2 and extracellular signal-regulated kinase 1/2 (ERK1/2), mitigated renal dysfunction, and ameliorated histopathological abnormalities. Additionally, trametinib significantly decreased macrophage infiltration and the expression of pro-inflammatory cytokines in the kidneys. It also lowered lipid peroxidation by-products, restored the reduced glutathione/oxidized glutathione ratio, and downregulated NADPH oxidase 4. Furthermore, trametinib significantly inhibited both apoptosis and necroptosis in the kidneys. In conclusion, our data underscore the potential of trametinib as a therapeutic agent for cisplatin-induced AKI, highlighting its role in reducing inflammation, oxidative stress, and tubular cell death.

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NADPH oxidase 4-SH3 domain-containing YSC84-like 1 complex participates liver inflammation and fibrosis

Hur,

Lee,

Yoo

et al. 2025

Free Radical Biology and Medicine

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Nox4-SH3YL1 complex is involved in diabetic nephropathy

Cited by 3 publications

References 59 publications

Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes

Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes

Efficacy of Trametinib in Alleviating Cisplatin-Induced Acute Kidney Injury: Inhibition of Inflammation, Oxidative Stress, and Tubular Cell Death in a Mouse Model

NADPH oxidase 4-SH3 domain-containing YSC84-like 1 complex participates liver inflammation and fibrosis

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