Mitochondrial ROS Triggers KIN Pathogenesis in FAN1-Deficient Kidneys

Airik, Merlin; Arbore, Haley; Childs, Elizabeth; Huynh, Amy B.; Phua, Yu Leng; Chen, Chi‐Wei; Aird, Katherine M.; Bharathi, Sivakama S.; Zhang, Bob; Conlon, Peter J.; Kmoch, Stanislav; Kidd, Kendrah; Bleyer, Anthony J.; Vockley, Jerry; Goetzman, Eric S.; Wipf, Peter; Airik, Rannar

doi:10.3390/antiox12040900

Cited by 5 publications

(2 citation statements)

References 60 publications

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“…Karyomegalic tubular cells failed to complete mitosis and underwent polyploidization [ 24 ]. FAN1 function in DNA repair appeared to be linked to mitochondrial energy metabolism in the kidney tubular epithelial cells owing to an increased sensitivity of FAN1 -deficient kidneys to mitochondrially derived oxygen stress [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…Also, the autopsy evaluation of livers did not reveal any change that could be specifically attributed to the mutational damage with exception of the mild and focal centrilobular fibrosis in patient B, which could well have been a consequence of ongoing liver cell injury. While KIN appears to be the result of genomic instability and mitotic abnormalities in tubular epithelial cells induced by homozygous mutations in the FNA1 DNA repair enzyme, and endogenous oxidative stress was demonstrated as a key source of DNA damage in FAN1 -deficient kidneys [ 25 ], the morphologic substrate and pathophysiology of liver disease in FAN1 -mutation remain an enigma.…”

Section: Discussionmentioning

confidence: 99%

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Phenotypic and Genotypic Features of the FAN1 Mutation-Related Disease in a Large Hungarian Family

Császár,

Kalmár,

Maróti

et al. 2024

IJMS

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Pathogenic variants in the FAN1 gene lead to a systemic disease with karyomegalic interstitial nephritis (KIN) at the forefront clinically. The phenotypic–genotypic features of a FAN1 mutation-related disease involving five members of a Hungarian Caucasian family are presented. Each had adult-onset chronic kidney disease of unknown cause treated with renal replacement therapy and elevated liver enzymes. Short stature, emaciation, latte-colored skin, freckles, and a hawk-like nose in four patients, a limited intellect in two patients, and chronic restrictive lung disease in one patient completed the phenotype. Severe infections occurred in four patients. All five patients had ceased. Four patients underwent autopsy. KIN and extrarenal karyomegaly were observed histologically; the livers showed no specific abnormality. The genotyping using formalin-fixed tissue samples detected a hitherto undescribed homozygous FAN1 mutation (c.1673_1674insT/p.Met558lfs*4; exon 5) in three of these patients and a heterozygous FAN1 mutation in one patient. The reason for the heterozygosity is discussed. In addition, 56 family members consented to the screening for FAN1 mutation from which 17 individuals proved to be heterozygous carriers; a blood chemistry evaluation of their kidney and liver function did not find any abnormality. The clinical presentation of FAN1-related disease was multifaceted, and not yet described manifestations were observed besides kidney and liver disease. Mutation in this gene should be suspected in adults with small kidneys of unknown cause, elevated liver enzymes, and recurrent infections, even without a family history.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phenotypic and Genotypic Features of the FAN1 Mutation-Related Disease in a Large Hungarian Family

Császár,

Kalmár,

Maróti

et al. 2024

IJMS

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A case of karyomegalic interstitial nephritis without FAN1 mutations in the setting of brentuximab, ifosfamide, and carboplatin exposure

Leong,

Dai,

Tong

et al. 2024

BMC Nephrol

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Shenqi Fuzheng Injection Reduces Cisplatin-Induced Kidney Injury via cGAS/STING Signaling Pathway in Breast Cancer Mice Model

Ma,

Bai,

Liu

et al. 2024

BCTT

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Background Shenqi Fuzheng Injection (SQFZ) is a traditional Chinese medicine injection consists of extracts of Codonopsis pilosula and Astragalus mongholicus . Combining SQFZ with conventional chemotherapy may improve the therapeutic efficacy and reduce side-effects of chemotherapy. However, the mechanisms of SQFZ reducing cisplatin-induced kidney injury are still unclear. Methods The main compounds of SQFZ were identified via UPLC-Q-TOF-MS technique. Using multiple databases to predict potential targets for SQFZ. We established a breast cancer model by injecting 4T1 cells into mice. Tumor growth and body weight were observed. Serum blood urea nitrogen (BUN), creatinine (CRE), and glutathione (GSH) levels were measured. The extent of their kidney injury was measured by hematoxylin-eosin staining (HE). Cell apoptosis was identified using Hoechst33258 staining, flow cytometry and TUNEL. We evaluated H2AX and stimulator of interferon genes (STING) expression by immunohistochemistry (IHC), and assessed apoptosis-associated proteins by Western blotting analysis. We also evaluated mitochondrial function. The secretion of the inflammatory cytokines in serum was observed using ELISA assay. The effect of the STING pathway in HK-2 renal tubular epithelial cells exposed to cisplatin alone or combined with SQFZ. Results The potential targets of SQFZ on kidney injury mainly related to inflammatory responses, oxidation and antioxidant, apoptosis as well as IFN signaling pathway. Cisplatin significantly reduced animal weight, while there were no changes in the combination SQFZ and cisplatin. SQFZ counteracted cisplatin-induced BUN and CRE elevation. SQFZ ameliorated the oxidative stress induced by cisplatin. It diminished cisplatin-induced apoptosis and mitochondrial DNA damage and reversed cisplatin-induced cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/STING signaling pathway activation. It also improved the mitochondrial dysfunction induced by cisplatin. Conclusions The results of the present study suggested that SQFZ effectively reduced cisplatin-induced kidney injury by inhibiting cGAS/STING signaling pathway.

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Mitochondrial ROS Triggers KIN Pathogenesis in FAN1-Deficient Kidneys

Cited by 5 publications

References 60 publications

Phenotypic and Genotypic Features of the FAN1 Mutation-Related Disease in a Large Hungarian Family

Phenotypic and Genotypic Features of the FAN1 Mutation-Related Disease in a Large Hungarian Family

A case of karyomegalic interstitial nephritis without FAN1 mutations in the setting of brentuximab, ifosfamide, and carboplatin exposure

Shenqi Fuzheng Injection Reduces Cisplatin-Induced Kidney Injury via cGAS/STING Signaling Pathway in Breast Cancer Mice Model

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