p53 in Proximal Tubules Mediates Chronic Kidney Problems after Cisplatin Treatment.
Shuangshuang FuXiaoru HuZhengwei MaQingqing WeiXiaohong XiangSiyao LiLu WenYumei LiangZheng DongPublished in: Cells (2022)
Nephrotoxicity is a major side-effect of cisplatin in chemotherapy, which can occur acutely or progress into chronic kidney disease (CKD). The protein p53 plays an important role in acute kidney injury induced by cisplatin, but its involvement in CKD following cisplatin exposure is unclear. Here, we address this question by using experimental models of repeated low-dose cisplatin (RLDC) treatment. In mouse proximal tubular BUMPT cells, RLDC treatment induced p53 activation, apoptosis, and fibrotic changes, which were suppressed by pifithrin-α, a pharmacologic inhibitor of p53. In vivo, chronic kidney problems following RLDC treatment were ameliorated in proximal tubule-specific p53-knockout mice (PT-p53-KO mice). Compared with wild-type littermates, PT-p53-KO mice showed less renal damage (KIM-1 positive area: 0.97% vs. 2.5%), less tubular degeneration (LTL positive area: 15.97% vs. 10.54%), and increased proliferation (Ki67 positive area: 2.42% vs. 0.45%), resulting in better renal function after RLDC treatment. Together, these results indicate that p53 in proximal tubular cells contributes significantly to the development of chronic kidney problems following cisplatin chemotherapy.
Keyphrases
- chronic kidney disease
- low dose
- acute kidney injury
- mental health
- oxidative stress
- cell cycle arrest
- metabolic syndrome
- signaling pathway
- type diabetes
- systemic sclerosis
- skeletal muscle
- cardiac surgery
- endoplasmic reticulum stress
- cell death
- locally advanced
- insulin resistance
- replacement therapy
- pi k akt
- neoadjuvant chemotherapy
- smoking cessation