Elevation of p53 sensitizes obese kidney to adriamycin-induced aberrant lipid homeostasis via repressing HNF4α-mediated FGF21 sensitivity
Introduction: Lipid metabolism disorders have been confirmed to be closely related to kidney injury caused by adriamycin (ADR) and obesity, respectively. However, it has not been explored whether lipid metabolism disorders appear progressively more severe after ADR-based chemotherapy in the obese st...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
|
| Series: | Journal of Advanced Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123224002996 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850261338571407360 |
|---|---|
| author | Jiahao Li Yufeng Tang Guangping Lu Qingbo Liu Yuanfang Guo Jie Wang Mengjie Xiao Ting Gao Xiaohui Zhang Junlian Gu |
| author_facet | Jiahao Li Yufeng Tang Guangping Lu Qingbo Liu Yuanfang Guo Jie Wang Mengjie Xiao Ting Gao Xiaohui Zhang Junlian Gu |
| author_sort | Jiahao Li |
| collection | DOAJ |
| description | Introduction: Lipid metabolism disorders have been confirmed to be closely related to kidney injury caused by adriamycin (ADR) and obesity, respectively. However, it has not been explored whether lipid metabolism disorders appear progressively more severe after ADR-based chemotherapy in the obese state, and the specific molecular mechanism needs to be further clarified. Objectives: This study was designed to examine the role of p53-fibroblast growth factor 21 (FGF21) axis in ADR-induced renal injury aggravated by high-fat diet (HFD). Methods: We engineered Fgf21 KO mice and used long-term (4 months) and short-term (0.5 months) HFD feeding, and ADR-injected mice, as well as STZ-induced type 1 diabetic mice and type 2 (db/db) diabetic mice to produce an in vivo model of nephrotoxicity. The specific effects of p53/FGF21 on the regulation of lipid metabolism disorders and its downstream mediators in kidney were subsequently elucidated using a combination of functional and pathological analysis, RNA-sequencing, molecular biology, and in vitro approaches. Results: Long-term HFD feeding mice exhibited compromised effects of FGF21 on alleviation of renal dysfunction and lipid accumulation following ADR administration. However, these impairments were reversed by p53 inhibitor (pifithrin-α, PFT-α). PFT-α sensitized FGF21 actions in kidney tissues, while knockout of Fgf21 impaired the protective effects of PFT-α on lipid metabolism. Mechanistically, p53 impaired the renal expression of FGF receptor-1 (FGFR1) and thereby developed gradually into FGF21 resistance via inhibiting hepatocyte nuclear factor 4 alpha (HNF4α)-mediated transcriptional activation of Fgfr1. More importantly, exogenous supplementation of FGF21 or PFT-α could not only alleviate ADR-induced lipid metabolism disorder aggravated by HFD, but also reduce lipid accumulation caused by diabetic nephropathy. Conclusion: Given the difficulties in developing the long-acting recombinant FGF21 analogs for therapeutic applications, sensitizing obesity-impaired FGF21 actions by suppression of p53 might be a therapeutic strategy for maintaining renal metabolic homeostasis during chemotherapy. |
| format | Article |
| id | doaj-art-a7eb91eed6e14f6d83d801c9871e3b01 |
| institution | OA Journals |
| issn | 2090-1232 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj-art-a7eb91eed6e14f6d83d801c9871e3b012025-08-20T01:55:27ZengElsevierJournal of Advanced Research2090-12322025-06-017216518010.1016/j.jare.2024.07.014Elevation of p53 sensitizes obese kidney to adriamycin-induced aberrant lipid homeostasis via repressing HNF4α-mediated FGF21 sensitivityJiahao Li0Yufeng Tang1Guangping Lu2Qingbo Liu3Yuanfang Guo4Jie Wang5Mengjie Xiao6Ting Gao7Xiaohui Zhang8Junlian Gu9School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaDepartment of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaSchool of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Corresponding author.Introduction: Lipid metabolism disorders have been confirmed to be closely related to kidney injury caused by adriamycin (ADR) and obesity, respectively. However, it has not been explored whether lipid metabolism disorders appear progressively more severe after ADR-based chemotherapy in the obese state, and the specific molecular mechanism needs to be further clarified. Objectives: This study was designed to examine the role of p53-fibroblast growth factor 21 (FGF21) axis in ADR-induced renal injury aggravated by high-fat diet (HFD). Methods: We engineered Fgf21 KO mice and used long-term (4 months) and short-term (0.5 months) HFD feeding, and ADR-injected mice, as well as STZ-induced type 1 diabetic mice and type 2 (db/db) diabetic mice to produce an in vivo model of nephrotoxicity. The specific effects of p53/FGF21 on the regulation of lipid metabolism disorders and its downstream mediators in kidney were subsequently elucidated using a combination of functional and pathological analysis, RNA-sequencing, molecular biology, and in vitro approaches. Results: Long-term HFD feeding mice exhibited compromised effects of FGF21 on alleviation of renal dysfunction and lipid accumulation following ADR administration. However, these impairments were reversed by p53 inhibitor (pifithrin-α, PFT-α). PFT-α sensitized FGF21 actions in kidney tissues, while knockout of Fgf21 impaired the protective effects of PFT-α on lipid metabolism. Mechanistically, p53 impaired the renal expression of FGF receptor-1 (FGFR1) and thereby developed gradually into FGF21 resistance via inhibiting hepatocyte nuclear factor 4 alpha (HNF4α)-mediated transcriptional activation of Fgfr1. More importantly, exogenous supplementation of FGF21 or PFT-α could not only alleviate ADR-induced lipid metabolism disorder aggravated by HFD, but also reduce lipid accumulation caused by diabetic nephropathy. Conclusion: Given the difficulties in developing the long-acting recombinant FGF21 analogs for therapeutic applications, sensitizing obesity-impaired FGF21 actions by suppression of p53 might be a therapeutic strategy for maintaining renal metabolic homeostasis during chemotherapy.http://www.sciencedirect.com/science/article/pii/S2090123224002996ObesityAdriamycinLipid metabolismFGF21 resistancep53 |
| spellingShingle | Jiahao Li Yufeng Tang Guangping Lu Qingbo Liu Yuanfang Guo Jie Wang Mengjie Xiao Ting Gao Xiaohui Zhang Junlian Gu Elevation of p53 sensitizes obese kidney to adriamycin-induced aberrant lipid homeostasis via repressing HNF4α-mediated FGF21 sensitivity Journal of Advanced Research Obesity Adriamycin Lipid metabolism FGF21 resistance p53 |
| title | Elevation of p53 sensitizes obese kidney to adriamycin-induced aberrant lipid homeostasis via repressing HNF4α-mediated FGF21 sensitivity |
| title_full | Elevation of p53 sensitizes obese kidney to adriamycin-induced aberrant lipid homeostasis via repressing HNF4α-mediated FGF21 sensitivity |
| title_fullStr | Elevation of p53 sensitizes obese kidney to adriamycin-induced aberrant lipid homeostasis via repressing HNF4α-mediated FGF21 sensitivity |
| title_full_unstemmed | Elevation of p53 sensitizes obese kidney to adriamycin-induced aberrant lipid homeostasis via repressing HNF4α-mediated FGF21 sensitivity |
| title_short | Elevation of p53 sensitizes obese kidney to adriamycin-induced aberrant lipid homeostasis via repressing HNF4α-mediated FGF21 sensitivity |
| title_sort | elevation of p53 sensitizes obese kidney to adriamycin induced aberrant lipid homeostasis via repressing hnf4α mediated fgf21 sensitivity |
| topic | Obesity Adriamycin Lipid metabolism FGF21 resistance p53 |
| url | http://www.sciencedirect.com/science/article/pii/S2090123224002996 |
| work_keys_str_mv | AT jiahaoli elevationofp53sensitizesobesekidneytoadriamycininducedaberrantlipidhomeostasisviarepressinghnf4amediatedfgf21sensitivity AT yufengtang elevationofp53sensitizesobesekidneytoadriamycininducedaberrantlipidhomeostasisviarepressinghnf4amediatedfgf21sensitivity AT guangpinglu elevationofp53sensitizesobesekidneytoadriamycininducedaberrantlipidhomeostasisviarepressinghnf4amediatedfgf21sensitivity AT qingboliu elevationofp53sensitizesobesekidneytoadriamycininducedaberrantlipidhomeostasisviarepressinghnf4amediatedfgf21sensitivity AT yuanfangguo elevationofp53sensitizesobesekidneytoadriamycininducedaberrantlipidhomeostasisviarepressinghnf4amediatedfgf21sensitivity AT jiewang elevationofp53sensitizesobesekidneytoadriamycininducedaberrantlipidhomeostasisviarepressinghnf4amediatedfgf21sensitivity AT mengjiexiao elevationofp53sensitizesobesekidneytoadriamycininducedaberrantlipidhomeostasisviarepressinghnf4amediatedfgf21sensitivity AT tinggao elevationofp53sensitizesobesekidneytoadriamycininducedaberrantlipidhomeostasisviarepressinghnf4amediatedfgf21sensitivity AT xiaohuizhang elevationofp53sensitizesobesekidneytoadriamycininducedaberrantlipidhomeostasisviarepressinghnf4amediatedfgf21sensitivity AT junliangu elevationofp53sensitizesobesekidneytoadriamycininducedaberrantlipidhomeostasisviarepressinghnf4amediatedfgf21sensitivity |