Transcriptomic analysis of rat kidney reveals a potential mechanism of sex differences in susceptibility to cisplatin-induced nephrotoxicity

被引:10
|
作者
Hwang, Da-Bin [1 ]
Cha, Min Ho [2 ]
Won, Dong-Hoon [1 ]
Shin, Yoo-Sub [1 ]
Kim, Shin-Young [1 ]
Kim, Changuk [1 ]
Lee, Eun-Ji [2 ]
Kim, Yoon Young [3 ]
Yun, Jun-Won [1 ,4 ]
机构
[1] Catholic Univ Korea, Dept Biotechnol, Bucheon 14662, South Korea
[2] Korea Inst Oriental Med, KM Applicat Ctr, Daegu 41062, South Korea
[3] Seoul Natl Univ Hosp, Dept Obstet & Gynecol, Seoul 03080, South Korea
[4] Catholic Univ Korea, Dept Med & Biol Sci, 43 Jibongro, Bucheon 14662, South Korea
基金
新加坡国家研究基金会;
关键词
Cisplatin; Nephrotoxicity; Multi-organ toxicity; Sex difference; Susceptibility; NITRIC-OXIDE; OXIDATIVE STRESS; PROTECTIVE ROLE; INDUCED LIVER; TESTOSTERONE; EXPRESSION; INJURY; CYTOCHROME-P450; BIOMARKERS; APOPTOSIS;
D O I
10.1016/j.freeradbiomed.2021.08.008
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Although cisplatin is an effective platinum-based anticancer drug against solid cancer, its availability is limited owing to its adverse side effects. Our study aimed to identify the potential relationship within cisplatin-induced multi-organ physiological changes and genetic factors associated with sex differences in nephrotoxicity susceptibility. To investigate this, mice received a single intraperitoneal injection of cisplatin. Cisplatin administration resulted in renal dysfunction, as evidenced by the elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine) and the degree of histopathological alterations. In particular, along with testicular damage and low testosterone levels, we also observed a decrease in male-specific (CYP3A2) or male-dominant (CYP2B1 and CYP3A1) CYP isoforms in the livers of rats with hepatotoxicity following cisplatin treatment, which may be associated with an imbalance in male hormone regulation caused by renal and testicular injury. Notably, we found that male rats were more susceptible to cisplatin-induced nephrotoxicity, as characterized by histopathological and biochemical analyses. Therefore, RNA sequencing was performed at baseline (pre-treatment) and at 48 h following cisplatin administration (post-treatment) to identify the genes associated with sex differences in nephrotoxicity susceptibility. Gap junctions, which play a role in replenishing damaged cells to maintain tissue homeostasis, and mismatch repair associated with a pathological apoptotic mechanism against cisplatin nephrotoxicity were significantly enriched only in males following cisplatin treatment. Moreover, among the 322 DEGs showing different basal expression patterns between males and females before cisplatin treatment, the male expressed high levels of genes, which are responsible for transmembrane transport and regulation of apoptotic process, pre-cisplatin treatment; additionally, genes involved in the PI3K-Akt signaling pathway and the oxidation-reduction process were significantly lower in males before cisplatin treatment. Collectively, our comprehensive findings provided valuable insight into the potential mechanisms of sex differences in cisplatin-induced nephrotoxicity susceptibility.
引用
收藏
页码:100 / 109
页数:10
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