NSD1-916aa encoded by CircNSD1 contributes to AKI-to-CKD transition through inducing ferroptosis in tubular epithelial cells
Li Gao, Junsheng Zhang, Chaoyi Chen, Sai Zhu, Xianglong Wei, Guiqin Tang, Sheng Wang, Yukai Wang, Xinran Liu, Ling Jiang, Yonggui Wu
Li Gao, Junsheng Zhang, Chaoyi Chen, Sai Zhu, Xianglong Wei, Guiqin Tang, Sheng Wang, Yukai Wang, Xinran Liu, Ling Jiang, Yonggui Wu
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Research Article Metabolism Nephrology

NSD1-916aa encoded by CircNSD1 contributes to AKI-to-CKD transition through inducing ferroptosis in tubular epithelial cells

Abstract

Acute kidney injury (AKI) is characterized by a rapid decline in renal function. In severe or recurrent cases, AKI can progress to chronic kidney disease (CKD), marked by renal inflammation and fibrosis. Despite the severity of these outcomes, early-stage diagnostic tools and pharmacological interventions for AKI-to-CKD progression remain limited. In this study, we examined circular RNA (circRNA) expression profiles in mouse renal cortex tissues 14 days after ischemia/reperfusion (I/R) injury using circRNA-Seq. The renal biopsy samples of patients after AKI exhibited reduced CircNSD1 expression, which was inversely associated with inflammation and fibrosis. Overexpression of CircNSD1 attenuated ferroptosis in vivo and in vitro, while slowing AKI-to-CKD progression. Mechanistically, CircNSD1 downregulated ACSL4 and SLC39A14 expression through histone H3 lysine 36 (H3K36) methylation, a critical pathway regulating ferroptosis after AKI or hypoxia/reoxygenation (H/R) injury. Furthermore, we identified that CircNSD1 encoded a NSD1-916aa peptide, which may functionally contribute to its observed effect. Collectively, these findings demonstrated that CircNSD1 may serve as a diagnostic and therapeutic target for early detection of AKI-to-CKD transition.

Authors

Li Gao, Junsheng Zhang, Chaoyi Chen, Sai Zhu, Xianglong Wei, Guiqin Tang, Sheng Wang, Yukai Wang, Xinran Liu, Ling Jiang, Yonggui Wu

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Figure 5

Overexpression of CircNSD1 decreases ferroptosis, inflammation, and fibrosis in Erastin-induced HK-2 cells.

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Overexpression of CircNSD1 decreases ferroptosis, inflammation, and fibr...
(A) An illustration of Erastin-induced HK-2 cells model. (B) Real-time PCR analysis of inflammation-related genes (TNFA, CCL2, and IL6) and fibrosis-related genes (TGFB1, COL1, and ASMA) in HK-2 cells after 48 hours of Erastin induction. (C) Representative electron micrographs of control and CircNSD1-overexpressing cells induced by Erastin. Scale bar: 500nm. (D)Levels of ferroptosis-related metabolites,including Fe2+, MDA, LPO and GSH in cells. (E) DCF assay and DHE assay in Erastin-induced CircNSD1 overexpressing cells and controls. Scale bar: 20μm. (F) Real-time PCR analysis of proinflammatory cytokines (TNFA, CCL2 and IL6) in control and CircNSD1 overexpressing cells after 48 hours of Erastin induction. (G) Real-time PCR analysis of fibrosis-related genes (TGFB1,COL1 and ASMA) in Erastin-treated control and CircNSD1 overexpressing cells. (H) Representative immunofluorescence staining of ASMA pictures in control and CircNSD1 overexpressing cells treated with Erastin. Scale bar: 20 μm. Data are shown as mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001 compared with the control by 1-way ANOVA with Tukey’s posthoc test. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with the EV-Erastain group by 1-way ANOVA with Tukey’s post hoc test.