TY - JOUR
T1 - p53 in Proximal Tubules Mediates Chronic Kidney Problems after Cisplatin Treatment
AU - Fu, Shuangshuang
AU - Hu, Xiaoru
AU - Ma, Zhengwei
AU - Wei, Qingqing
AU - Xiang, Xiaohong
AU - Li, Siyao
AU - Wen, Lu
AU - Liang, Yumei
AU - Dong, Zheng
N1 - Funding Information:
Funding: This research was funded by the US National Institutes of Health (DK058831 and DK087843), the Department of Veterans Affairs (Merit Review Award I01 BX000319), and the National Natural Science Foundation of China (Grant 81800679). Z.D. is the recipient of a Senior Research Career Scientist award from the US Department of Veterans Affairs.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Chronic kidney disease
KW - Cisplatin
KW - Fibrosis
KW - Nephrotoxicity
KW - P53
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U2 - 10.3390/cells11040712
DO - 10.3390/cells11040712
M3 - Article
C2 - 35203361
AN - SCOPUS:85124948010
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 4
M1 - 712
ER -