Increased Nrf2 expression by renal cell carcinoma is associated with postoperative chronic kidney disease and an unfavorable prognosis
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Hideo Yuki1,*, Takao Kamai1,*, Satoshi Murakami1,2, Satoru Higashi3, Takahiro Narimatsu1, Tsunehito Kambara1, Hironori Betsunoh1, Hideyuki Abe1, Kyoko Arai1, Hiromichi Shirataki3 and Ken-Ichiro Yoshida1
1Department of Urology, Dokkyo Medical University, Mibu, Tochigi, Japan
2Division of Field Application, Life Technologies, Tokyo, Japan
3Department of Molecular and Cell Biology, Dokkyo Medical University, Mibu, Tochigi, Japan
*These authors have contributed equally to this work
Takao Kamai, email: firstname.lastname@example.org
Keywords: nuclear factor erythroid 2–related factor 2 (Nrf2); chronic kidney disease (CKD); renal cell cancer
Received: December 04, 2017 Accepted: April 17, 2018 Published: June 19, 2018
Chronic kidney disease (CKD) is a worldwide health problem, and prevention of CKD is important for preservation of renal function after kidney surgery. There is evidence that transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2) has a vital antioxidant and detoxifying role in protecting the kidneys against various diseases. Impaired activation of Nrf2 is associated with oxidative stress related to CKD, and Nrf2 is also a key player in the development of cancer. However, the clinical impact of Nrf2 has not been investigated in patients with renal cell carcinoma (RCC). A retrospective study was performed in 89 patients undergoing nephrectomy for RCC. The estimated glomerular filtration rate (eGFR) and serum uric acid (SUA) were investigated over time after surgery. We investigated Nrf2 protein expression in all tumors and single nucleotide polymorphisms (SNPs) of the Nrf2 gene in 7 tumors. In patients whose tumors showed higher Nrf2 expression, there was a more rapid decrease of eGFR and increase of SUA after nephrectomy. Multivariate analysis confirmed that increased Nrf2 expression was an independent poor prognostic factor related to shorter overall survival. Among the 7 tumor samples, an SNP on exon 5 of the Nrf2 gene in one tumor and three genotypes (C/C, C/A, and A/A) of rs6721961 at the promoter region of the Nrf2 gene were observed. Although the mechanisms underlying the influence of Nrf2 are still unclear, our findings suggested that elevated tumor expression of Nrf2 was associated with postoperative CKD and biologically aggressive RCC with an unfavorable prognosis.
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