p53 in Proximal Tubules Mediates Chronic Kidney Problems after Cisplatin Treatment
Shuangshuang Fu,
Xiaoru Hu,
Zhengwei Ma,
Qingqing Wei,
Xiaohong Xiang,
Siyao Li,
Lu Wen,
Yumei Liang,
Zheng Dong
Affiliations
Shuangshuang Fu
Laboratory of Kidney Disease, Department of Nephrology, Hunan Provincial People’s Hospital (The First-Affiliated Hospital of Hunan Normal University), Changsha Clinical Research Center for Kidney Disease, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha 410005, China
Xiaoru Hu
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Zhengwei Ma
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Qingqing Wei
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Xiaohong Xiang
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Siyao Li
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Lu Wen
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Yumei Liang
Laboratory of Kidney Disease, Department of Nephrology, Hunan Provincial People’s Hospital (The First-Affiliated Hospital of Hunan Normal University), Changsha Clinical Research Center for Kidney Disease, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha 410005, China
Zheng Dong
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
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.
