A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis

Guan, Yuting; Liang, Xiujie; Ma, Ziyuan; Hu, Hailong; Liu, Hongbo; Miao, Zhen; Linkermann, Andreas; Hellwege, Jacklyn N.; Voight, Benjamin F.; Suszták, Katalin

doi:10.1038/s41467-021-25377-x

Cited by 54 publications

(56 citation statements)

References 64 publications

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“…As Nec-1 is known to also inhibit ferroptosis ( 22 ), in retrospect, we consider it possible that the beneficial effects of Nec-1 on the CI-AKI model may be due to ferroptosis modulation rather than inhibition of receptor-interacting protein kinase 1 (RIPK1). Furthermore, a recent study identified single-nucleotide polymorphisms (SNPs) in close proximity to the DPEP1 gene to be frequently associated with AKI to chronic kidney disease progression in a large patient cohort ( 48 ). In addition, carnosine dipeptidase II (CNDP2) was demonstrated to protect cells under cysteine insufficiency by hydroliyzing GSH-related peptides ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor–induced dipeptidase-1 expression and glutathione depletion

et al. 2022

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Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)–dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced increase in tubular necrosis in freshly isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase in DPEP1 expression and GSH depletion. Together, we identified a previously unknown mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications.

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Section: Discussionmentioning

confidence: 99%

Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor–induced dipeptidase-1 expression and glutathione depletion

et al. 2022

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“…DPEP1 plays a role in glutathione metabolism and has recently been implicated in ferroptosis, a key process in the pathogenesis of AKI ( 7 , 25 , 32 ). Thus, the reduction in leukocyte recruitment and inflammation observed following DPEP1 inhibition or deficiency during IRI may be an indirect result of DPEP1 effects on tubular injury and death.…”

Section: Resultsmentioning

confidence: 99%

Dipeptidase-1 governs renal inflammation during ischemia reperfusion injury

et al. 2022

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The mechanisms that drive leukocyte recruitment to the kidney are incompletely understood. Dipeptidase-1 (DPEP1) is a major neutrophil adhesion receptor highly expressed on proximal tubular cells and peritubular capillaries of the kidney. Renal ischemia reperfusion injury (IRI) induces robust neutrophil and monocyte recruitment and causes acute kidney injury (AKI). Renal inflammation and the AKI phenotype were attenuated in Dpep1 −/− mice or mice pretreated with DPEP1 antagonists, including the LSALT peptide, a nonenzymatic DPEP1 inhibitor. DPEP1 deficiency or inhibition primarily blocked neutrophil adhesion to peritubular capillaries and reduced inflammatory monocyte recruitment to the kidney after IRI. CD44 but not ICAM-1 blockade also decreased neutrophil recruitment to the kidney during IRI and was additive to DPEP1 effects. DPEP1, CD44, and ICAM-1 all contributed to the recruitment of monocyte/macrophages to the kidney following IRI. These results identify DPEP1 as a major leukocyte adhesion receptor in the kidney and potential therapeutic target for AKI.

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“…In a 2021 study by Guan et al, eQTL, mQTL and ATAC-seq data were used to fine-map the region of rs164748, which was identified in GWAS for estimated glomerular filtration rate (eGFR). In this study, genome editing in mice was used to demonstrate that there are at least two genes, DPEP1 and CHMP1A, involved in the regulation of ferroptosis and that they surprisingly had the opposite effects on a trait [228]. The study illustrated that a GWAS LD-region could contain multiple causal genetic factors.…”

Section: Narrow-focus Follow-up Studiesmentioning

confidence: 99%

Bench Research Informed by GWAS Results

Kondratyev

Алфимова

Golov

et al. 2021

Cells

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Scientifically interesting as well as practically important phenotypes often belong to the realm of complex traits. To the extent that these traits are hereditary, they are usually ‘highly polygenic’. The study of such traits presents a challenge for researchers, as the complex genetic architecture of such traits makes it nearly impossible to utilise many of the usual methods of reverse genetics, which often focus on specific genes. In recent years, thousands of genome-wide association studies (GWAS) were undertaken to explore the relationships between complex traits and a large number of genetic factors, most of which are characterised by tiny effects. In this review, we aim to familiarise ‘wet biologists’ with approaches for the interpretation of GWAS results, to clarify some issues that may seem counterintuitive and to assess the possibility of using GWAS results in experiments on various complex traits.

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A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis

Cited by 54 publications

References 64 publications

Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor–induced dipeptidase-1 expression and glutathione depletion

Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor–induced dipeptidase-1 expression and glutathione depletion

Dipeptidase-1 governs renal inflammation during ischemia reperfusion injury

Bench Research Informed by GWAS Results

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