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 2

CircNSD1 expression is suppressed in vivo, in vitro, and in patients.

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CircNSD1 expression is suppressed in vivo, in vitro, and in patients. (...
(A) Results of high-throughput circRNA-Seq in kidney tissues from control and I/R-14D mice. (B) Relative expression of circRNA detected by real time-PCR from 2 days to 6 weeks after I/R injury. Data are shown as mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001 compared with the control or CircNsd1 group by 1-way ANOVA with Tukey’s post hoc test. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with the I/R-2D group by 1-way ANOVA with Tukey’s post hoc test. (C) FISH assay for CircNSD1. Scale bar: 100 μm (red), 50 μm (white). (D) An illustration of H/R-induced HK-2 cells model. (E) Examination of CircNSD1 in circBase (http://circbase.org/) via Sanger sequencing. (F) Real-time PCR analysis of CircNSD1 and parental gene NSD1, digested by RNase R. Data are shown as mean ± SEM, ***P < 0.001 compared with RNase R- RF1 group by 1-way ANOVA with Tukey’s post hoc test. (G) FISH assay for CircNSD1 in HK-2 cells and H/R-induced HK-2 cells. Scale bar: 20 μm (white). (H) CircNSD1 was detected in serum of control group and patients after AKI. Data are shown as mean ± SEM, ***P < 0.001 compared with Control group by Student’s t test. (I) FISH for CircNSD1 in renal biopsies from controls and patients after AKI. Scale bar: 100 μm (white); 50 μm (black). (J) IHC for CD68+ reveals the inflammatory response, and ASMA reveals fibrosis in renal biopsies from controls and patients with AKI-to-CKD. Scale bar: 100 μm (black). (K) Correlation analysis between CircNSD1 in renal biopsies and the inflammatory response (CD68+) or fibrosis (ASMA) in patients after AKI. (L) Correlation analysis between CircNSD1 in serum and the inflammatory response (CD68+) or fibrosis (ASMA) in renal biopsies from patients after AKI.