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FSTL1 aggravates high glucose-induced oxidative stress and transdifferentiation in HK-2 cells
Baoyuan Zhang1,2, Hang Geng3, Kai Zhao2,4
1Department of Histology and Embryology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China.
Abstract:
Chronic hyperglycemia, a hallmark of diabetes, can trigger inflammatory responses in the kidney, leading to diabetic nephropathy (DN). Follistatin-like protein 1 (FSTL1) has emerged as a potential therapeutic target in various kidney diseases. This study investigated the effect of high glucose on FSTL1 expression and its role in oxidative stress and cellular transdifferentiation injury in HK-2 human proximal tubule epithelial cells, a model of DN. We investigated FSTL1's level in HK-2 cells exposed to high glucose using Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). FSTL1 was manipulated using recombinant human FSTL1 (rhFSTL1) or lentiviral shFSTL1. We then analyzed proliferation, oxidative stress, transdifferentiation, cell migration, and the nuclear factor kappa-B (NF-κB) signaling pathway potentially involved in FSTL1 effects. Finally, we blocked the NF-κB pathway to see its influence on these cellular processes. High glucose exposure significantly increased FSTL1 in HK-2 cells, with longer/higher glucose further amplifying this effect. Silencing of FSTL1 ameliorates cellular damage by promoting proliferation, enhancing superoxide dismutase (SOD) and glutathione (GSH) activity, and reducing malondialdehyde (MDA) production, inhibiting cell migration. Furthermore, it prevented the harmful conversion of HK-2 cells from epithelial to myofibroblast-like phenotypes, evidenced by decreased fibronectin (FN) and α-smooth muscle actin (α-SMA) and preserved E-cadherin. Notably, silencing FSTL1 also inhibited the NF-κB signaling pathway. Conversely, rhFSTL1 exhibited opposite effects. Importantly, blocking NF-κB reversed the detrimental effects of FSTL1. These findings suggest that FSTL1 contributes to high glucose-induced kidney injury by promoting oxidative stress and cellular transdifferentiation potentially via the NF-κB pathway. Targeting FSTL1 may represent a novel therapeutic strategy for preventing or mitigating DN progression.
Insights
Follistatin-like protein 1 (FSTL1) exacerbates diabetic kidney disease by increasing oxidative stress and cell changes. Inhibiting FSTL1 may offer a new therapeutic approach for diabetic nephropathy (DN).
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Diabetic nephropathy (DN) is a severe complication of diabetes, characterized by chronic hyperglycemia and kidney inflammation.
- Follistatin-like protein 1 (FSTL1) is implicated in kidney disease pathogenesis and presents a potential therapeutic target.
Purpose of the Study:
- To investigate the role of FSTL1 in high glucose-induced kidney injury.
- To explore FSTL1's impact on oxidative stress, cellular transdifferentiation, and the NF-κB pathway in a diabetic nephropathy model.
Main Methods:
- HK-2 human proximal tubule epithelial cells were exposed to high glucose conditions.
- FSTL1 expression was analyzed using Western blotting and qRT-PCR.
- FSTL1 levels were manipulated via rhFSTL1 and lentiviral shFSTL1; cellular proliferation, oxidative stress markers (SOD, GSH, MDA), transdifferentiation markers (FN, α-SMA, E-cadherin), cell migration, and the NF-κB pathway were assessed. NF-κB was blocked to evaluate its role.
Main Results:
- High glucose significantly increased FSTL1 expression in HK-2 cells.
- Silencing FSTL1 reduced oxidative stress, inhibited cell migration, and prevented epithelial-to-myofibroblast transdifferentiation, while promoting proliferation.
- FSTL1 silencing inhibited the NF-κB pathway, and blocking NF-κB reversed FSTL1-induced detrimental effects.
Conclusions:
- FSTL1 significantly contributes to high glucose-induced kidney injury by promoting oxidative stress and cellular transdifferentiation, mediated through the NF-κB pathway.
- Targeting FSTL1 presents a promising novel therapeutic strategy for mitigating diabetic nephropathy progression.
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