Whole Blood Metabolomic Profiling of Mice with Tacrolimus-Induced Chronic Nephrotoxicity: NAD<sup>+</sup> Depletion with Salvage Pathway Impairment
Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) is a serious issue for long-term graft survival in kidney transplantation. However, the pathophysiology of TAC nephrotoxicity remains unclear. In this study, we analyzed whole blood samples from mice that developed TAC nephrotoxici...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/14/1/62 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832589254656524288 |
|---|---|
| author | Sho Nishida Tamaki Ishima Daiki Iwami Ryozo Nagai Kenichi Aizawa |
| author_facet | Sho Nishida Tamaki Ishima Daiki Iwami Ryozo Nagai Kenichi Aizawa |
| author_sort | Sho Nishida |
| collection | DOAJ |
| description | Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) is a serious issue for long-term graft survival in kidney transplantation. However, the pathophysiology of TAC nephrotoxicity remains unclear. In this study, we analyzed whole blood samples from mice that developed TAC nephrotoxicity in order to discover its mechanism. Mice were divided into a TAC group and a control group (<i>n</i> = 5 per group). The TAC group received TAC subcutaneously (1 mg/kg/day for 28 days), while the control group received normal saline instead. After the administration period, whole blood was collected and metabolomic analysis was performed, revealing significant changes in 56 metabolites. The major metabolic changes were related to uremic toxins, vascular damage, and NAD<sup>+</sup>. NAD<sup>+</sup> levels were significantly lower in the TAC group, and ADP-ribose, nicotinamide, and nicotinamide N-oxide, which are degradation products of NAD<sup>+</sup>, were significantly higher, suggesting impairment of the NAD<sup>+</sup> salvage pathway. NAD<sup>+</sup> deficiency suggests cellular aging and mitochondrial dysfunction, which may induce vascular damage and chronic kidney disease. Our study demonstrated a correlation between low NAD<sup>+</sup> levels and the pathophysiology of TAC nephrotoxicity. |
| format | Article |
| id | doaj-art-49a77d1e708343cf870bdc6a500513b6 |
| institution | Kabale University |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj-art-49a77d1e708343cf870bdc6a500513b62025-01-24T13:19:21ZengMDPI AGAntioxidants2076-39212025-01-011416210.3390/antiox14010062Whole Blood Metabolomic Profiling of Mice with Tacrolimus-Induced Chronic Nephrotoxicity: NAD<sup>+</sup> Depletion with Salvage Pathway ImpairmentSho Nishida0Tamaki Ishima1Daiki Iwami2Ryozo Nagai3Kenichi Aizawa4Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, JapanDivision of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, JapanDivision of Renal Surgery and Transplantation, Department of Urology, Jichi Medical University, Shimotsuke 329-0498, JapanJichi Medical University, Shimotsuke 329-0498, JapanDivision of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, JapanTacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) is a serious issue for long-term graft survival in kidney transplantation. However, the pathophysiology of TAC nephrotoxicity remains unclear. In this study, we analyzed whole blood samples from mice that developed TAC nephrotoxicity in order to discover its mechanism. Mice were divided into a TAC group and a control group (<i>n</i> = 5 per group). The TAC group received TAC subcutaneously (1 mg/kg/day for 28 days), while the control group received normal saline instead. After the administration period, whole blood was collected and metabolomic analysis was performed, revealing significant changes in 56 metabolites. The major metabolic changes were related to uremic toxins, vascular damage, and NAD<sup>+</sup>. NAD<sup>+</sup> levels were significantly lower in the TAC group, and ADP-ribose, nicotinamide, and nicotinamide N-oxide, which are degradation products of NAD<sup>+</sup>, were significantly higher, suggesting impairment of the NAD<sup>+</sup> salvage pathway. NAD<sup>+</sup> deficiency suggests cellular aging and mitochondrial dysfunction, which may induce vascular damage and chronic kidney disease. Our study demonstrated a correlation between low NAD<sup>+</sup> levels and the pathophysiology of TAC nephrotoxicity.https://www.mdpi.com/2076-3921/14/1/62tacrolimus (TAC)TAC nephrotoxicityNAD<sup>+</sup>metabolomicschronic kidney disease biomarkersADMA |
| spellingShingle | Sho Nishida Tamaki Ishima Daiki Iwami Ryozo Nagai Kenichi Aizawa Whole Blood Metabolomic Profiling of Mice with Tacrolimus-Induced Chronic Nephrotoxicity: NAD<sup>+</sup> Depletion with Salvage Pathway Impairment Antioxidants tacrolimus (TAC) TAC nephrotoxicity NAD<sup>+</sup> metabolomics chronic kidney disease biomarkers ADMA |
| title | Whole Blood Metabolomic Profiling of Mice with Tacrolimus-Induced Chronic Nephrotoxicity: NAD<sup>+</sup> Depletion with Salvage Pathway Impairment |
| title_full | Whole Blood Metabolomic Profiling of Mice with Tacrolimus-Induced Chronic Nephrotoxicity: NAD<sup>+</sup> Depletion with Salvage Pathway Impairment |
| title_fullStr | Whole Blood Metabolomic Profiling of Mice with Tacrolimus-Induced Chronic Nephrotoxicity: NAD<sup>+</sup> Depletion with Salvage Pathway Impairment |
| title_full_unstemmed | Whole Blood Metabolomic Profiling of Mice with Tacrolimus-Induced Chronic Nephrotoxicity: NAD<sup>+</sup> Depletion with Salvage Pathway Impairment |
| title_short | Whole Blood Metabolomic Profiling of Mice with Tacrolimus-Induced Chronic Nephrotoxicity: NAD<sup>+</sup> Depletion with Salvage Pathway Impairment |
| title_sort | whole blood metabolomic profiling of mice with tacrolimus induced chronic nephrotoxicity nad sup sup depletion with salvage pathway impairment |
| topic | tacrolimus (TAC) TAC nephrotoxicity NAD<sup>+</sup> metabolomics chronic kidney disease biomarkers ADMA |
| url | https://www.mdpi.com/2076-3921/14/1/62 |
| work_keys_str_mv | AT shonishida wholebloodmetabolomicprofilingofmicewithtacrolimusinducedchronicnephrotoxicitynadsupsupdepletionwithsalvagepathwayimpairment AT tamakiishima wholebloodmetabolomicprofilingofmicewithtacrolimusinducedchronicnephrotoxicitynadsupsupdepletionwithsalvagepathwayimpairment AT daikiiwami wholebloodmetabolomicprofilingofmicewithtacrolimusinducedchronicnephrotoxicitynadsupsupdepletionwithsalvagepathwayimpairment AT ryozonagai wholebloodmetabolomicprofilingofmicewithtacrolimusinducedchronicnephrotoxicitynadsupsupdepletionwithsalvagepathwayimpairment AT kenichiaizawa wholebloodmetabolomicprofilingofmicewithtacrolimusinducedchronicnephrotoxicitynadsupsupdepletionwithsalvagepathwayimpairment |