2. Academic Validation
  3. LATS1 inhibitor and zinc supplement synergistically ameliorates contrast-induced acute kidney injury: Induction of Metallothionein-1 and suppression of tubular ferroptosis

LATS1 inhibitor and zinc supplement synergistically ameliorates contrast-induced acute kidney injury: Induction of Metallothionein-1 and suppression of tubular ferroptosis

  • Free Radic Biol Med. 2024 Jul 20:223:42-52. doi: 10.1016/j.freeradbiomed.2024.07.019.
Bo Dai 1,  Xuan Liu 2,  Mengwei Du 2,  Shuangshuang Xie 3,  Lin Dou 4,  Xue Mi 2,  Donghui Zhou 2,  Yu Su 2,  Tianyu Shen 2,  Yuying Zhang 2,  Shijing Yue 2,  Dekun Wang 5,  Xiaoyue Tan 6
Affiliations

Affiliations

  • 1 Department of Pathology, The School of Medicine, Nankai University, No. 94 Weijin Road, Nankai District, Tianjin, 300071, China; Department of Pathology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Qingyang District, Chengdu, Sichuan province, 610072, China.
  • 2 Department of Pathology, The School of Medicine, Nankai University, No. 94 Weijin Road, Nankai District, Tianjin, 300071, China.
  • 3 Departments of Radiological Image, Tianjin First Central Hospital, No. 24 Fukang Road, Tianjin, 300191, China.
  • 4 Departments of Intensive Care Unit, Tianjin First Central Hospital, No. 24 Fukang Road, Tianjin, 300191, China.
  • 5 Department of Pathology, The School of Medicine, Nankai University, No. 94 Weijin Road, Nankai District, Tianjin, 300071, China. Electronic address: wangdekun@nankai.edu.cn.
  • 6 Department of Pathology, The School of Medicine, Nankai University, No. 94 Weijin Road, Nankai District, Tianjin, 300071, China. Electronic address: xiaoyuetan@nankai.edu.cn.
PMID: 39033829 DOI: 10.1016/j.freeradbiomed.2024.07.019
Abstract

Contrast-induced acute kidney injury (CI-AKI) is a prevalent cause of renal dysfunction among hospitalized patients, yet the precise pathogenesis and effective therapeutic strategies remain elusive. In this study, we investigated the role of tubular Ferroptosis in both experimental CI-AKI models and in primary tubular epithelial cells (PTECs) treated with ioversol. Using whole exome Sequencing, we identified metallothioneins (MTs) as being among the most significantly downregulated genes following ioversol exposure. Our findings reveal that overexpression of MT1 mitigates, whereas suppression of Mt-1 exacerbates, ioversol-induced tubular Ferroptosis. Interestingly, the level of MTF1 (metal regulatory transcription factor 1), a principal regulator of MT1, was found to increase in response to ioversol treatment. We further elucidated that ioversol activates LATS1 (Large tumor suppressor homolog 1), a kinase that promotes the phosphorylation and nuclear translocation of MTF1, thereby inhibiting its transcriptional activity for MT1. Both genetic and pharmacological inhibition of LATS1 reversed the ioversol-induced suppression of Mt-1. From a therapeutic perspective, the LATS1 inhibitor TDI-011536, in combination with zinc acetate, was administered to a rodent model of CI-AKI. Our data indicate that this combination synergistically upregulates MT1 expression and provides protection against contrast media-induced tubular Ferroptosis. In summary, our study demonstrates that the reduction of Mt-1 contributes to tubular Ferroptosis associated with CI-AKI. We show that contrast media activate LATS1, which in turn suppresses the transcriptional activity of MTF1 for MT1. Herein, the combination of zinc acetate and a LATS1 inhibitor emerges as a potential therapeutic approach for the treatment of CI-AKI.

Keywords

Contrast-induced acute kidney disease; Ferroptosis; Large tumor suppressor homolog 1; Metal regulatory transcription factor 1; Metallothionein-1.

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