Zahedi Kamyar, Barone Sharon, Brooks Marybeth, Stewart Tracy Murray, Foley Jackson R, Nwafor Ashley, Casero Robert A, Soleimani Manoocher
Division of Nephrology, Department of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Research Services, New Mexico Veterans Health Care Center, Albuquerque, NM 87108, USA.
Biomedicines. 2024 Mar 13;12(3):640. doi: 10.3390/biomedicines12030640.
Cisplatin, a chemotherapeutic agent, can cause nephrotoxic and ototoxic injuries. Using a mouse model of repeated low dose cisplatin (RLDC), we compared the kidneys of cisplatin- and vehicle-treated mice on days 3 (early injury phase) and 35 (late injury/recovery phase) after the final treatment. RNA-seq analyses revealed increases in the expression of markers of kidney injury (e.g., lipocalin 2 and kidney injury molecule 1) and fibrosis (e.g., collagen 1, fibronectin, and vimentin 1) in RLDC mice. In addition, we observed increased expression of polyamine catabolic enzymes (spermidine/spermine N-acetyltransferase, , and spermine oxidase, ) and decreased expression of ornithine decarboxylase (), a rate-limiting enzyme in polyamine synthesis in mice subjected to RLDC. Upon confirmation of the RNA-seq results, we tested the hypothesis that enhanced polyamine catabolism contributes to the onset of renal injury and development of fibrosis. To test our hypothesis, we compared the severity of RLDC-induced renal injury and fibrosis in wildtype (WT), -KO, and -KO mice. Our results suggest that the ablation of polyamine catabolic enzymes reduces the severity of renal injury and that modulation of the activity of these enzymes may protect against kidney damage and fibrosis caused by cisplatin treatment.
顺铂是一种化疗药物，可导致肾毒性和耳毒性损伤。我们使用重复低剂量顺铂（RLDC）小鼠模型，在末次给药后第3天（早期损伤阶段）和第35天（晚期损伤/恢复阶段）比较了顺铂处理组和溶剂处理组小鼠的肾脏。RNA测序分析显示，RLDC小鼠肾损伤标志物（如lipocalin 2和肾损伤分子1）和纤维化标志物（如胶原蛋白1、纤连蛋白和波形蛋白1）的表达增加。此外，我们观察到RLDC处理的小鼠中多胺分解代谢酶（亚精胺/精胺N-乙酰转移酶和精胺氧化酶）的表达增加，而鸟氨酸脱羧酶（多胺合成中的限速酶）的表达减少。在证实RNA测序结果后，我们检验了增强的多胺分解代谢导致肾损伤发生和纤维化发展这一假设。为了验证我们的假设，我们比较了野生型（WT）、-KO和-KO小鼠中RLDC诱导的肾损伤和纤维化的严重程度。我们的结果表明，多胺分解代谢酶的缺失降低了肾损伤的严重程度，并且调节这些酶的活性可能预防顺铂治疗引起的肾损伤和纤维化。
