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Войти в исследования Life sciences · 2025
Zinc protoporphyrin-triggered ferroptosis plays a critical role in renal proximal tubular cell damage and chronic kidney disease.
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Tsai Li-Ting, Wang Ching-Chia, Liu Chieh-Yun, Chiang Chih-Kang, Liu Shing-Hwa
Аннотация
BACKGROUND: Chronic kidney disease (CKD) represents a significant global health concern. Zinc protoporphyrin (ZnPP), a byproduct formed during disrupted iron metabolism, is frequently elevated in individuals with renal dysfunction. The contribution of ZnPP to kidney pathology remains inadequately understood. Here, we investigated the role of ZnPP in CKD progression in vitro and in vivo.
METHODS: A adenine-induced CKD mouse model and the renal tubular epithelial cell lines (HK-2 and NRK-52E) were used. In some experiments, CKD mice were treated with the N,N,N',N'-tetrakis (2-pyridinylmethyl)-1,2-ethanediamine (TPEN), a potent zinc chelator as a ZnPP inhibitor. The ferroptosis-related signaling molecules were determined.
RESULTS: ZnPP accumulation, iron overload, ferroptotic activity, and kidney damage, including fibrosis, in CKD mouse kidneys were observed. In vitro, ZnPP exposure increased intracellular labile iron and reactive oxygen species, ultimately inducing ferroptosis in tubular cells. ZnPP disrupted iron regulation by enhancing iron uptake through the upregulation of transferrin and divalent metal transporter 1, while suppressing iron storage and export via reduced expression of ferritin heavy chain and ferroportin. The iron chelator deferoxamine significantly mitigated ZnPP-induced iron accumulation, oxidative stress, and cell death. ZnPP also markedly increased heme oxygenase (HO) activity and HO-1 protein expression in renal tubular cells. Administration of TPEN substantially reduced renal ZnPP levels and alleviated ferroptosis and kidney injury in CKD mice.
CONCLUSION: These findings highlight ZnPP as a previously unrecognized driver of ferroptosis via HO-1 overactivation and dysregulated iron metabolism in CKD, and suggest that targeting ZnPP-mediated pathways may offer a novel therapeutic strategy for CKD.
METHODS: A adenine-induced CKD mouse model and the renal tubular epithelial cell lines (HK-2 and NRK-52E) were used. In some experiments, CKD mice were treated with the N,N,N',N'-tetrakis (2-pyridinylmethyl)-1,2-ethanediamine (TPEN), a potent zinc chelator as a ZnPP inhibitor. The ferroptosis-related signaling molecules were determined.
RESULTS: ZnPP accumulation, iron overload, ferroptotic activity, and kidney damage, including fibrosis, in CKD mouse kidneys were observed. In vitro, ZnPP exposure increased intracellular labile iron and reactive oxygen species, ultimately inducing ferroptosis in tubular cells. ZnPP disrupted iron regulation by enhancing iron uptake through the upregulation of transferrin and divalent metal transporter 1, while suppressing iron storage and export via reduced expression of ferritin heavy chain and ferroportin. The iron chelator deferoxamine significantly mitigated ZnPP-induced iron accumulation, oxidative stress, and cell death. ZnPP also markedly increased heme oxygenase (HO) activity and HO-1 protein expression in renal tubular cells. Administration of TPEN substantially reduced renal ZnPP levels and alleviated ferroptosis and kidney injury in CKD mice.
CONCLUSION: These findings highlight ZnPP as a previously unrecognized driver of ferroptosis via HO-1 overactivation and dysregulated iron metabolism in CKD, and suggest that targeting ZnPP-mediated pathways may offer a novel therapeutic strategy for CKD.