Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule

Deng, Fei; Sharma, Isha; Dai, Yingbo; Yang, Ming; Kanwar, Yashpal S.

doi:10.1172/jci129903

Cited by 149 publications

(131 citation statements)

References 49 publications

(86 reference statements)

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“…Here, it is conceivable that MI deficiency worsens the renal homeostasis, as elegantly surmised by Chang et al (28). Nevertheless, the data included in RESULTS also suggest that other factors, e.g., oxidant stress, play a significant role in the progression of renal injury, as described in cisplatin-induced AKI models (30,47).…”

Section: Discussionmentioning

confidence: 88%

Myo-inositol Oxygenase (MIOX) Overexpression Drives the Progression of Renal Tubulointerstitial Injury in Diabetes

et al. 2020

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Conceivably, upregulation of myo -inositol oxygenase (MIOX) is associated with altered cellular redox. Its promoter includes oxidant-response elements, and we also discovered binding sites for XBP1, a transcription factor of endoplasmic reticulum (ER) stress response. Previous studies indicate that MIOX’s upregulation in acute tubular injury is mediated by oxidant and ER stress. Here, we investigated whether hyperglycemia leads to accentuation of oxidant and ER stress while these boost each other’s activities, thereby augmenting tubulointerstitial injury/fibrosis. We generated MIOX-overexpressing transgenic (MIOX-TG) and MIOX knockout (MIOX-KO) mice. A diabetic state was induced by streptozotocin administration. Also, MIOX-KO were crossbred with Ins2 Akit a to generate Ins2 Akita /KO mice. MIOX-TG mice had worsening renal functions with kidneys having increased oxidant/ER stress, as reflected by DCF/dihydroethidium staining, perturbed NAD-to-NADH and glutathione-to-glutathione disulfide ratios, increased NOX4 expression, apoptosis and its executionary molecules, accentuation of TGF-β signaling, Smads and XBP1 nuclear translocation, expression of GRP78 and XBP1 (ER stress markers), and accelerated tubulointerstitial fibrosis. These changes were not seen in MIOX-KO mice. Interestingly, such changes were remarkably reduced in Ins2 Akita /KO mice and, likewise, in vitro experiments with XBP1 siRNA. These findings suggest that MIOX expression accentuates, while its deficiency shields kidneys from, tubulointerstitial injury by dampening oxidant and ER stress, which mutually enhance each other’s activity.

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Section: Discussionmentioning

confidence: 88%

Myo-inositol Oxygenase (MIOX) Overexpression Drives the Progression of Renal Tubulointerstitial Injury in Diabetes

et al. 2020

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“…Many studies revealed that apoptosis, necroptosis as well as ferroptosis all contribute to cisplatin-induced tubular cell death and AKI [24][25][26] . In this study, we firstly used terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and anticleaved caspase 3 immunofluorescent staining to identify cell apoptosis in the kidney tissues.…”

Section: Specific Deletion Of Rheb1 In Tubular Cells Promotes Cisplatmentioning

confidence: 99%

Rheb1 protects against cisplatin-induced tubular cell death and acute kidney injury via maintaining mitochondrial homeostasis

Wang

Gui

et al. 2020

Cell Death Dis

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Ras homolog enriched in brain (Rheb1), a small GTPase, plays a crucial role in regulating cell growth, differentiation, and survival. However, the role and mechanisms for Rheb1 in tubular cell survival and acute kidney injury (AKI) remain unexplored. Here we found that Rheb1 signaling was activated in kidney tubule of AKI patients and cisplatin-treated mice. A mouse model of tubule-specific deletion of Rheb1 (Tubule-Rheb1 −/−) was generated. Compared to control littermates, Tubule-Rheb1 −/− mice were phenotypically normal within 2 months after birth but developed more severe kidney dysfunction, tubular cell death including apoptosis, necroptosis and ferroptosis, mitochondrial defect and less PGC-1α expression after cisplatin injection. In primary cultured tubular cells, Rheb1 ablation exacerbated cisplatin-induced cell death and mitochondrial defect. Furthermore, haploinsufficiency for Tsc1 in tubular cells led to Rheb1 activation and mitigated cisplatin-induced cell death, mitochondrial defect and AKI. Together, this study uncovers that Rheb1 may protect against cisplatin-induced tubular cell death and AKI through maintaining mitochondrial homeostasis.

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“…In addition to the crosstalk between ferroptosis and other forms of cell death, the function and assay of ferroptosis related molecular and pathway need to be investigated. Some newly reported proteins such as PEBP1 [15], NCOA4 [16], and metallothionein-1G [17] are correlated with ferroptosis via iron metabolism and lipid peroxidation. In our GO and KEGG analysis, we found that the gene co-expressed with ACSL4 is enriched in the pathway of protein ubiquitination.…”

Section: Discussionmentioning

confidence: 98%

Identification of ACSL4 as a biomarker and contributor of ferroptosis in clear cell renal cell carcinoma

Guo¹

2020

Preprint

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Background ACSL4 has been reported to be related to tumor genesis and involved in the processes of ferroptosis. However, the expression levels and prognostic value of ACSL4 in clear cell renal cell carcinoma (ccRCC) remain unclear. Methods The Oncomine and TCGA databases were used to predict the expression of ACSL4 mRNA in ccRCC and its association with ccRCC prognosis. The expression levels of ACSL4 were determined in human RCC tissues by real-time PCR. Kaplan-Meier curves were used to analyze the diagnostic and prognostic significance of ACSL4 in ccRCC. A ferroptosis inducer (erastin) was used to investigate the effects of ACSL4 on ferroptosis in ccRCC cell lines. Results The expression level of ACSL4 was significantly down-regulated in ccRCC tissues (P < 0.001), which was consistent with the analysis of the Oncomine and TCGA database. Then, immunohistochemical results demonstrated that the ACSL4 was weak or not detected in ccRCC tissues than that in normal tissues. ACSL4 differential expression level was significantly related to gender, ccRCC subtypes, nodal invasion, tumor grade and cancer stages (all P < 0.001). Survival analysis revealed that overall survival was favorable in ccRCC patients with ACSL4 high expression (P = 0.014). Overexpression of ACSL4 by gene transfection restores ferroptosis sensitization in cancer cells, whereas suppression of ACSL4 expression by RNAi increases ferroptosis resistance. Mechanically, protein ubiquitination may be involved in ACSL4-mediated ferroptosis. Conclusions As a monitor and contributor of ferroptosis, ACSL4 was decreased in ccRCC and served as a useful diagnostic and prognostic biomarker, which will be a new potential therapeutic target for ccRCC.

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Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule

Cited by 149 publications

References 49 publications

Myo-inositol Oxygenase (MIOX) Overexpression Drives the Progression of Renal Tubulointerstitial Injury in Diabetes

Myo-inositol Oxygenase (MIOX) Overexpression Drives the Progression of Renal Tubulointerstitial Injury in Diabetes

Rheb1 protects against cisplatin-induced tubular cell death and acute kidney injury via maintaining mitochondrial homeostasis

Identification of ACSL4 as a biomarker and contributor of ferroptosis in clear cell renal cell carcinoma

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