Investigating the reno-protective effect of tamoxifen on ischemia-reperfusion injury through regulation of amino acid transporter and lipid accumulation- focusing on renal tubular cells and pericytes (I) = 探討泰莫西芬經由調控胺基酸運輸蛋白及減少脂肪堆積而產生對急性缺血再灌流腎損傷的保護作用-聚焦腎小管細胞及血管周細胞研究 (I)

Project title
探討泰莫西芬經由調控胺基酸運輸蛋白及減少脂肪堆積而產生對急性缺血再灌流腎損傷的保護作用-聚焦腎小管細胞及血管周細胞研究 (I)
Internal ID
NHRI-EX113-11316SC
Principal Investigator
Start Date
January 1, 2024
End Date
December 31, 2024
Organizations
Partner Organizations
National Health Research Institutes
Keywords
chronic kidney disease
acute kidney injury
tamoxifen
amino acid metabolism
lipid metabolism
renal tubular cell
pericyte
Description
With the aging population and numerous new drugs, image studies with contrast, and surgeries that could affect kidney function, the incidence of acute kidney injury (AKI) is increasing and is the leading cause of chronic kidney disease (CKD), which increases the risk of death and many complications, resulting in a significant burden on individuals, society, and the entire healthcare system. Currently, there are no safe and effective drugs available to prevent or treat AKI. Only by conducting more research and understanding the mechanism of AKI, and developing effective drugs can we effectively reduce the harm caused by AKI. There are three reasons why the mechanism of AKI has not been translated into effective clinical treatment. First, the causes of AKI are diverse, and the mechanism may not be the same. Second, there are many mechanisms of AKI, and giving drugs targeting a single mechanism may not be successful. Third, AKI changes rapidly, and the pathogenic mechanisms at different time points may not be the same. The timing of drug administration must be accurate to achieve efficacy. In summary, the treatment of AKI is complex, because AKI changes vary and requires multiple drugs to work together or a single drug with multiple therapeutic mechanisms given at the appropriate time to effectively reduce the damage caused by AKI. In other words, before suitable therapeutic drugs are available, prevention of AKI is the best strategy. Our team has previously found that if tamoxifen is given to mice as a pretreatment before ischemia-reperfusion-induced AKI, the severity of their AKI is lower, but the mechanism is complex and requires further study. Tamoxifen is a drug that has been used in the treatment of breast cancer. The role and mechanism of these drugs in kidney diseases such as AKI are still unclear. Our previous project used translating ribosome affinity purification (TRAP) followed by RNA sequencing technology (TRAP-SEQ) to isolate renal tubular cells, and single-nuclei RNA sequencing analysis found that amino acid transport proteins such as Slc7a12 increased in the renal tubular cells of mice given tamoxifen. Some kidney and tumor cell studies have found that enhancing amino acid metabolism improves AKI and promotes tumor cell proliferation and metastasis. However, there is limited research on the kidney, and most studies focus only on intracellular amino acid metabolism. There is no research on the impact of amino acid transporters on amino acid metabolism during AKI. Therefore, one of the main objectives of this study is to investigate the effect of amino acid transporters on amino acid metabolism and associated mechanisms such as oxidative stress, inflammatory response, and mitochondrial function in AKI. We hypothesize that tamoxifen can improve kidney protection by promoting an increase in amino acid transporters, thereby improving amino acid metabolism. On the other hand, from our previous transcriptome sequencing results of tubular cells, we found that uridine diphosphate glucuronic acid transferase (UGT), particularly Ugt1a2, was significantly increased after tamoxifen administration. UGT is generally involved in the metabolism and elimination of certain drugs or small molecules. There has been more research on this topic in the liver, and much less in the kidney. Lipid accumulation can inhibit the repair of renal tubular cells. Additionally, previous studies have found that UGT can eliminate lipid accumulation. Therefore, we speculate that tamoxifen may promote fatty acid excretion by increasing UGT in renal tubules to reduce lipid accumulation. Another objective of this study is to investigate how metabolic changes in pericytes during AKI affect their activation and proliferation, because our previous research has found that inactivated pericytes after AKI still maintain a pro-inflammatory and pro-fibrotic phenotype, which can lead to subsequent kidney fibrosis. In our transcriptomic analysis of pericytes during AKI, we also found an increase in amino acid transporters and UGT, and we speculate that these changes are related to metabolic changes in pericytes. There has been very little research on metabolic changes in pericytes after AKI, and we believe that our previous results can serve as a foundation for future studies, which could be highly beneficial for drug development and further research. The above studies on the effects of tamoxifen on amino acid transporters and UGT in renal tubular cells provide insights into the renal protective effects of tamoxifen. This not only gives us more confidence in using tamoxifen in future clinical trials, but also helps in the development of related drugs. Furthermore, the study on the metabolic changes of pericytes in AKI opens up new avenues of research. Our research may reduce the incidence of end-stage renal disease and alleviate the burden on patients, families, and society. The topics addressed in this project involve public health issues such as AKI/CKD and metabolic-related diseases, so we believe that this project fits into research areas such as 2-Cardiovascular and metabolic disorders or 8-Health policy and social welfare.

臺大位居世界頂尖大學之列，為永久珍藏及向國際展現本校豐碩的研究成果及學術能量，圖書館整合機構典藏（NTUR）與學術庫（AH）不同功能平台，成為臺大學術典藏NTU scholars。期能整合研究能量、促進交流合作、保存學術產出、推廣研究成果。

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