Review
Physiology
Andrew M. Hall, Sophie de Seigneux
Summary: Damage to the proximal tubule is the most common cause of acute kidney injury in humans. Current diagnostic and treatment options are limited, and a deeper understanding of pathogenic mechanisms at a cellular level is needed. Recent studies have shown significant changes in proximal tubule metabolism during acute kidney injury, highlighting potential targets for intervention. This article emphasizes the current state of the field and highlights three emerging areas worthy of attention: axial heterogeneity in determining baseline susceptibility, insult specific pathogenic mechanisms, and the link between tubular metabolism and whole-body homeostasis.
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2022)
Review
Pediatrics
Sian E. Piret, Sandeep K. Mallipattu
Summary: This article discusses the transcriptional regulation mechanisms of specific metabolic pathways in normal proximal tubules and acute kidney injury, as well as highlighting the current knowledge gaps and challenges that need to be addressed.
PEDIATRIC NEPHROLOGY
(2022)
Article
Multidisciplinary Sciences
Louisa M. S. Gerhardt, Jing Liu, Kari Koppitch, Pietro E. Cippa, Andrew P. McMahon
Summary: The study found that even mild to moderate ischemia-reperfusion injury can cause lasting damage, spreading from the cortico-medullary boundary (CMB) to cortical regions, and the remaining failed-repair PTCs may be triggers for chronic disease progression.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Endocrinology & Metabolism
Min Liu, Yanhui Yang, Yajin Liu, Xiaoyue Peng, Yi Hou, Xuejiao Zhang, Haipeng Sun, Chunyan Shan
Summary: This study found that serum BCAA levels decline gradually with the progression of DKD in T2DM patients, and they are independently correlated with renal function indicators. These findings suggest that serum BCAA concentrations may serve as a crucial predictor for both the initiation and progression of DKD.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Review
Cell Biology
Michaela E. Trautman, Nicole E. Richardson, Dudley W. Lamming
Summary: The proportion of people suffering from age-related diseases is increasing worldwide. Recent research has shown that low protein diets, particularly those low in branched-chain amino acids (BCAAs), can reduce mortality and promote metabolic health and extended lifespan in both humans and rodents. This article discusses the emerging evidence that BCAAs play a crucial role in healthy metabolism and longevity, and explores the physiological and molecular mechanisms behind the benefits of restricting dietary BCAAs. The findings suggest that the quality of protein, specifically the composition of dietary protein, may be a previously overlooked factor in metabolic dysfunction and reducing dietary BCAAs could be a promising new approach to delaying and preventing age-related diseases.
Article
Urology & Nephrology
Yasuhiro Yoshimura, Yoshiharu Muto, Kohei Omachi, Jeffrey H. Miner, Benjamin D. Humphreys
Summary: This study reveals the regulatory mechanisms of HNF4A and HNF4G during human proximal tubule differentiation. The experimental strategy can be applied more broadly to investigate transcriptional regulation in human kidney development.
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2023)
Article
Pharmacology & Pharmacy
Tiangang Wu, Mengling Wang, Fengling Ning, Shilin Zhou, Xuetao Hu, Hong Xin, Svetlana Reilly, Xuemei Zhang
Summary: Fibrosis, characterized by excessive production of extracellular matrix, is a common pathological feature of organ diseases. Metabolic alterations, especially in the regulation of branched-chain amino acids (BCAAs), have been found to play significant roles in fibrogenesis. Dysregulation of BCAAs metabolism has been implicated in various diseases. This review summarizes the metabolic regulation of fibrosis, changes in BCAAs metabolism associated with fibrosis, and the effects and mechanisms of BCAAs intervention in hepatic, renal, and cardiac fibrosis, with a focus on liver fibrosis and associated hepatocellular carcinoma.
PHARMACOLOGICAL RESEARCH
(2023)
Review
Genetics & Heredity
Can Chen, Hassan Naveed, Keping Chen
Summary: This article introduces the important role of branched-chain amino acid aminotransferases in cellular metabolism, summarizes the related research in animals, plants, microorganisms, and humans, and analyzes the molecular mechanism. It has been found that disorders in branched-chain amino acid metabolism are closely related to various diseases, especially tumor development.
FRONTIERS IN GENETICS
(2023)
Article
Nutrition & Dietetics
Katarzyna Paczkowska, Dominik Rachon, Andrzej Berg, Jacek Rybka, Katarzyna Kapczynska, Marek Bolanowski, Jacek Daroszewski
Summary: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that predisposes women to metabolic disturbances. Recent research suggests that alterations in amino acid profiles may be indicative of metabolic disorders. This study found elevated levels of aromatic amino acids in PCOS women, and significant differences in amino acid concentrations between metabolically healthy and unhealthy obesity subgroups of PCOS women.
Article
Nutrition & Dietetics
Huan Xu, Xuanyang Wang, Xiaoqing Xu, Lin Liu, Yuntao Zhang, Xuemin Yan, Yingfeng Zhang, Keke Dang, Ying Li
Summary: This study using Mendelian randomization analysis found that increased circulating levels of BCAAs were associated with an increased risk of squamous cell lung cancer, but no causal link was found between BCAAs and other types of cancer.
CLINICAL NUTRITION
(2023)
Article
Medicine, General & Internal
M. H. Mahbub, Natsu Yamaguchi, Yuki Nakagami, Ryosuke Hase, Hidekazu Takahashi, Yasutaka Ishimaru, Rie Watanabe, Hiroyuki Saito, Junki Shimokawa, Hiroshi Yamamoto, Shinya Kikuchi, Tsuyoshi Tanabe
Summary: The study found significant positive associations of plasma isoleucine, leucine, and phenylalanine levels with declining kidney function, suggesting their potential as biomarkers for evaluating kidney function decline. Future longitudinal studies should further investigate the causal relationship between altered levels of these amino acids and impaired kidney function.
JOURNAL OF CLINICAL MEDICINE
(2021)
Article
Nutrition & Dietetics
Yuyan Liu, Chengwen Zhang, Yuan Zhang, Xuheng Jiang, Yuanhong Liang, Huan Wang, Yongfang Li, Guifan Sun
Summary: This study aimed to investigate the relationship between dietary intake of branched-chain amino acids (BCAAs) and hypertension risk in the Chinese population. The findings showed that dietary BCAAs intake was positively associated with both systolic and diastolic blood pressure values, as well as an increased risk of hypertension.
Article
Urology & Nephrology
Jan Klocke, Seung Joon Kim, Christopher M. Skopnik, Christian Hinze, Anastasiya Boltengagen, Diana Metzke, Emil Grothgar, Luka Prskalo, Leonie Wagner, Paul Freund, Nina Goerlich, Frederic Muench, Kai M. Schmidt-Ott, Mir-Farzin Mashreghi, Christine Kocks, Kai-Uwe Eckardt, Nikolaus Rajewsky, Philipp Enghard
Summary: This study demonstrates the feasibility and potential of using urine for single-cell transcriptomics to investigate the cellular and molecular dynamics of acute kidney injury (AKI). The findings provide unprecedented insights into the processes underlying AKI and open up new opportunities for target identification, sub-categorization, and monitoring of the disease.
KIDNEY INTERNATIONAL
(2022)
Review
Immunology
Berkay Yahsi, Gurcan Gunaydin
Summary: Immunometabolism, especially in terms of augmenting anti-tumor immune responses, has been extensively researched. Regulatory T cells (Tregs) are known for their immunosuppressive roles in anti-tumor immune responses. Targeting Tregs specifically in the tumor microenvironment (TME) is crucial for successful and specific treatment. Recent studies have shown an association between Tregs and isoleucine, which may play a major role in affecting Tregs. Targeting the immunometabolic pathways of Tregs could be a rational approach for treatment.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Medicine, General & Internal
Xiaohong Xiang, Jiefu Zhu, Gang Zhang, Zhengwei Ma, Man J. Livingston, Zheng Dong
Summary: The study demonstrates that p53 plays a critical role in kidney injury associated with cold storage/transplantation, and inhibiting p53 can improve the histology and function of transplanted kidneys, showing potential as a therapeutic target for kidney transplantation.
FRONTIERS IN MEDICINE
(2021)
Article
Medicine, Research & Experimental
Ricardo Melo Ferreira, Angela R. Sabo, Seth Winfree, Kimberly S. Collins, Danielle Janosevic, Connor J. Gulbronson, Ying-Hua Cheng, Lauren Casbon, Daria Barwinska, Michael J. Ferkowicz, Xiaoling Xuei, Chi Zhang, Kenneth W. Dunn, Katherine J. Kelly, Timothy A. Sutton, Takashi Hato, Pierre C. Dagher, Tarek M. El-Achkar, Michael T. Eadon
Summary: This study characterized the transcriptomic signature of cell types within the kidney and found that the spatial distribution of acute kidney injury (AKI) affects cells heterogeneously. By mapping different cell types to human nephrectomy, the researchers were able to predict cell-type spots that corresponded with histopathology. Furthermore, the study identified localized regions of reduced overall expression associated with injury pathways in murine AKI models.
Article
Urology & Nephrology
Sian E. Piret, Ahmed A. Attallah, Xiangchen Gu, Yiqing Guo, Nehaben A. Gujarati, Justina Henein, Amy Zollman, Takashi Hato, Avi Ma'ayan, Monica P. Revelo, Kathleen G. Dickman, Chung-Hsin Chen, Chia-Tung Shun, Thomas A. Rosenquist, John C. He, Sandeep K. Mallipattu
Summary: The loss of proximal tubule-specific KLF15 exacerbates acute kidney injury and fibrosis, likely due to the loss of interaction with PPAR alpha leading to the loss of FAO gene transcription.
KIDNEY INTERNATIONAL
(2021)
Article
Cardiac & Cardiovascular Systems
Arvin Halim, Gayatri Narayanan, Takashi Hato, Lilun Ho, Douglas Wan, Andrew M. Siedlecki, Eugene P. Rhee, Andrew S. Allegretti, Sagar U. Nigwekar, Daniel Zehnder, Thomas F. Hiemstra, Joseph Bonventre, David M. Charytan, Sahir Kalim, Ravi Thadhani, Tzongshi Lu, Kenneth Lim
Summary: Failure of the myocardium in advanced chronic kidney disease is characterized by impairment of the cytoskeleton, disruption of the focal adhesion pathway, mitochondrial failure, and loss of cell survival pathways.
JOURNAL OF THE AMERICAN HEART ASSOCIATION
(2022)
Article
Oncology
Kotoko Yamatani, Tomohiko Ai, Kaori Saito, Koya Suzuki, Atsushi Hori, Sonoko Kinjo, Kazuho Ikeo, Vivian Ruvolo, Weiguo Zhang, Po Yee Mak, Bogumil Kaczkowski, Hironori Harada, Kazuhiro Katayama, Yoshikazu Sugimoto, Jered Myslinski, Takashi Hato, Takashi Miida, Marina Konopleva, Yoshihide Hayashizaki, Bing Z. Carter, Yoko Tabe, Michael Andreeff
Summary: BCL2A1 was found to be overexpressed in FLT3-ITD/D835 mutated AML cells, leading to resistance to TKIs. By inhibiting STAT5, type I TKI gilteritinib alleviated TKI resistance of FLT3-ITD/D835. The combination of gilteritinib and venetoclax showed synergistic effects in FLT3-ITD/D835 positive AML cells. BCL2A1 may be a potential novel therapeutic target in treating FLT3-ITD/D835 mutated AML.
TRANSLATIONAL ONCOLOGY
(2022)
Article
Cell Biology
Kimberly S. Collins, Michael T. Eadon, Ying-Hua Cheng, Daria Barwinska, Ricardo Melo Ferreira, Thomas W. McCarthy, Danielle Janosevic, Farooq Syed, Bernhard Maier, Tarek M. El-Achkar, Katherine J. Kelly, Carrie L. Phillips, Takashi Hato, Timothy A. Sutton, Pierre C. Dagher
Summary: This study found that alterations in protein translation and carboxylic acid catabolism in the proximal tubule are key features in both human and murine DKD.
Article
Orthopedics
Keith G. Avin, James M. Dominguez, Neal X. Chen, Takashi Hato, Jered J. Myslinski, Hongyu Gao, Yunlong Liu, Todd O. McKinley, Krista M. Brown, Sharon M. Moe, Roman M. Natoli
Summary: By analyzing bone marrow tissue samples of patients with femoral nonunions using single-cell RNA sequencing, gene expression differences associated with osteoimmunology were identified. These findings contribute to a better understanding of the pathogenesis of nonunion fractures and provide a clinical rationale for further research in the field of osteoimmunology.
JOURNAL OF ORTHOPAEDIC RESEARCH
(2023)
Article
Urology & Nephrology
Ashley Kidwell, Shiv Pratap Singh Yadav, Bernhard Maier, Amy Zollman, Kevin Ni, Arvin Halim, Danielle Janosevic, Jered Myslinski, Farooq Syed, Lifan Zeng, Alain Bopda Waffo, Kimihiko Banno, Xiaoling Xuei, Emma H. Doud, Pierre C. Dagher, Takashi Hato
Summary: This study reveals that translation shutdown in late-phase sepsis-induced kidney injury is caused by excessive phosphorylation of eIF2 alpha and sustained by reduced expression of the counter-regulatory phosphatase Ppp1r15a. Overcoming the repression of Ppp1r15a enables translation salvage and improves kidney function in an endotoxemia model. The existence of an upstream open reading frame (uORF) in Ppp1r15a is a potential therapeutic target for rescuing translation in late-phase sepsis.
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2023)
Editorial Material
Immunology
Kenneth Lim, Neal Chen, Takashi Hato
Article
Medicine, Research & Experimental
Yang Lin, Kimihiko Banno, Chang-Hyun Gil, Jered Myslinski, Takashi Hato, William C. . Shelley, Hongyu Gao, Xiaoling Xuei, Yunlong Liu, David P. . Basile, Momoko Yoshimoto, Nutan Prasain, Stefan P. Tarnawsky, Ralf H. Adams, Katsuhiko Naruse, Junko Yoshida, Michael P. . Murphy, Kyoji Horie, Mervin C. . Yoder
Summary: Most circulating endothelial cells undergo apoptosis, but rare circulating endothelial colony-forming cells (C-ECFCs) with proliferative and vasculogenic activity can be cultured. This study revealed that murine C-ECFCs emerged in the early postnatal period, possessed high vasculogenic potential with enriched frequency of clonal proliferative cells compared with tissue-resident ECFCs, and were not derived from the BM hematopoietic system but from tissue-resident ECFCs. In humans, C-ECFCs were present in the CD34bright cord blood mononuclear subset, exhibited proliferative potential and in vivo vasculogenic function, and showed a single cell transcriptome similar to umbilical venous endothelial cells.
Article
Urology & Nephrology
Sian E. E. Piret
Summary: Members of the Kruppel-like family of transcription factors are expressed widely, including in the kidney, and their expression may change in acute kidney injury, resulting in effects on various cellular pathways. This mini-review focuses on the roles of KLF6 and KLF15 in controlling proximal tubular cell metabolism.
Article
Physiology
Kaice A. LaFavers, Chadi A. Hage, Varun Gaur, Radmila Micanovic, Takashi Hato, Shehnaz Khan, Seth Winfree, Simit Doshi, Ranjani N. Moorthi, Homer Twigg, Xue-Ru Wu, Pierre C. Dagher, Edward F. Srour, Tarek M. El-Achkar
Summary: The kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function through the release of Tamm-Horsfall protein, suggesting potential therapeutic applications in sepsis.
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Takehiro Hasegawa, Takashi Hato, Toshitsugu Okayama, Kazuho Ikeo, Yoshiaki Miyamoto, Niina Iwanaga, Kohjin Suzuki, Maho Yoshida, Kazuto Yamashita, Saya Yamashita, Eiya Tamada, Abdullah Khasawneh, Faith Jessica Paran, Rieko Oyama, Toshio Naito, Kenta Noda, Yoko Tabe
Summary: This study investigated the association between cytokine endotypes and cell-mediated immunity in severe cases of COVID-19. The study identified four clusters of COVID-19 cases based on severity, with two clusters showing potential as prognostic references for targeted treatment. The study also observed signs of T cell exhaustion in a certain cluster.
EUROPEAN CYTOKINE NETWORK
(2022)
Review
Oncology
Samrat Das, Shefali Thakur, Michael Korenjak, Viktoriya S. Sidorenko, Felicia Fei-Lei Chung, Jiri Zavadil
Summary: In this Review, Das et al. describe the evidence for aristolochic acid as a potent carcinogen and explore the impact of public health measures on preventing aristolochic acid-linked cancers and nephropathy, with a call to action for the implementation of further preventative measures.
NATURE REVIEWS CANCER
(2022)
