KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease

Mori, Yutaro; Ajay, Amrendra K.; Chang, Jae‐Hyung; Mou, Shan; Zhao, Hongxia; Kishi, Seiji; Li, Jiahua; Brooks, Craig R.; Xiao, Sheng; Woo, Heung‐Myong; Sabbisetti, Venkata; Palmer, Suetonia C.; Galichon, Pierre; Li, Li; Henderson, Joel M.; Kuchroo, Vijay K.; Hawkins, Julie; Ichimura, Takaharu; Bonventre, Joseph V.

doi:10.1016/j.cmet.2021.04.004

Cited by 142 publications

(117 citation statements)

References 87 publications

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“…We have found that KIM-1 serves as a receptor for full length replication-competent SARS-CoV-2, SARS-CoV-2 spike protein expressing pseudovirus and virosomes, and that virosome uptake and pseudovirus infection are inhibited by anti-KIM-1 antibodies or TW-37, an inhibitor for KIM-1-mediated endocytosis 22 .…”

Section: Discussionmentioning

confidence: 99%

“…2b) as assessed by confocal microscopy and quantified by flow cytometry. Cellular uptake of virosomes was efficiently inhibited by treatment with anti-KIM-1 IgG or with TW-37, our newly discovered inhibitor for KIM-1-mediated endocytosis 22 (Fig. 2c).…”

Section: The Role Of Kim-1 In Promoting Sars-cov-2 Entry In Lung Alveolar Epithelial Cellsmentioning

confidence: 94%

“…We have developed a method to generate epithelial KIM-1 expressing "tubuloids" from kidney tissue derived from human subjects 22 . Human primary epithelial cell cultures were established from the nontumor kidney tissue removed from patients with kidney cancer.…”

Section: Three-dimensional Human Renal Epithelial Tubuloids Take Up Virosomesmentioning

confidence: 99%

“…We have recently identified TW-37 as an inhibitor of KIM-1-mediated oxidized lipid and palmitic acid (bound to albumin) uptake 22 .…”

Section: Introductionmentioning

confidence: 99%

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KIM-1/TIM-1 is a Receptor for SARS-CoV-2 in Lung and Kidney

Mori

Fink

Ichimura

et al. 2020

Preprint

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SARS-CoV-2 precipitates respiratory distress by infection of airway epithelial cells and is often accompanied by acute kidney injury. We report that Kidney Injury Molecule-1/T cell immunoglobulin mucin domain 1 (KIM-1/TIM-1) is expressed in lung and kidney epithelial cells in COVID-19 patients and is a receptor for SARS-CoV-2. Human and mouse lung and kidney epithelial cells express KIM-1 and endocytose nanoparticles displaying the SARS-CoV-2 spike protein (virosomes). Uptake was inhibited both by anti-KIM-1 antibodies and by TW-37, our newly discovered inhibitor of KIM-1-mediated endocytosis. Enhanced KIM-1 expression by human kidney tubuloids increased uptake of virosomes. KIM-1 positive cells express less angiotensin-converting enzyme 2 (ACE2), the well-known receptor for SARS-CoV-2. Using microscale thermophoresis, the EC50 for KIM-1-SARS-CoV-2 spike protein, and receptor binding domain (RBD) interactions, were 19 and 10 nM respectively. Thus KIM-1 is an alternative receptor to ACE2 for SARS-CoV-2. KIM-1 targeted therapeutics may prevent and/or treat COVID-19.

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Section: Discussionmentioning

confidence: 99%

Section: The Role Of Kim-1 In Promoting Sars-cov-2 Entry In Lung Alveolar Epithelial Cellsmentioning

confidence: 94%

Section: Three-dimensional Human Renal Epithelial Tubuloids Take Up Virosomesmentioning

confidence: 99%

“…We have recently identified TW-37 as an inhibitor of KIM-1-mediated oxidized lipid and palmitic acid (bound to albumin) uptake 22 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

KIM-1/TIM-1 is a Receptor for SARS-CoV-2 in Lung and Kidney

Mori

Fink

Ichimura

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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“…The activation of inflammasomes in podocytes is also important in glomerular lesions of diabetic kidney disease [26,27]. In addition, there are some reports of inflammasome activation in tubular cells [28,29]. In the future, it will be necessary to use cell-specific genetically modified animals to clarify this issue, or bone marrow transplantation experiments could help to dissolve this issue.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Dysfunction Accelerates Impairment of Mitochondrial Function in Ageing Kidneys via Inflammasome Activation

Wada

Umeno

Nagasu

et al. 2021

IJMS

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Chronic kidney disease is a common problem in the elderly and is associated with increased mortality. We have reported on the role of nitric oxide, which is generated from endothelial nitric oxide synthase (eNOS), in the progression of aged kidneys. To elucidate the role of endothelial dysfunction and the lack of an eNOS-NO pathway in ageing kidneys, we conducted experiments using eNOS and ASC-deficient mice. C57B/6 J mice (wild type (WT)), eNOS knockout (eNOS KO), and ASC knockout (ASC KO) mice were used in the present study. Then, eNOS/ASC double-knockout (eNOS/ASC DKO) mice were generated by crossing eNOS KO and ASC KO mice. These mice were sacrificed at 17−19 months old. The Masson positive area and the KIM-1 positive area tended to increase in eNOS KO mice, compared with WT mice, but not eNOS/ASC DKO mice. The COX-positive area was significantly reduced in eNOS KO mice, compared with WT and eNOS/ASC DKO mice. To determine whether inflammasomes were activated in infiltrating macrophages, the double staining of IL-18 and F4/80 was performed. IL-18 and F4/80 were found to be co-localised in the tubulointerstitial areas. Inflammasomes play a pivotal role in inflammaging in ageing kidneys. Furthermore, inflammasome activation may accelerate cellular senescence via mitochondrial dysfunction. The importance of endothelial function as a regulatory mechanism suggests that protection of endothelial function may be a potential therapeutic target.

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Metabolic reprogramming heterogeneity in chronic kidney disease

Miguel

Kramann

2023

FEBS Open Bio

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Fibrosis driven by excessive accumulation of extracellular matrix (ECM) is the hallmark of chronic kidney disease (CKD). Myofibroblasts, which are the cells responsible for ECM production, are activated by cross talk with injured proximal tubule and immune cells. Emerging evidence suggests that alterations in metabolism are not only a feature of but also play an influential role in the pathogenesis of renal fibrosis. The application of omics technologies to cell‐tracing animal models and follow‐up functional data suggest that cell‐type‐specific metabolic shifts have particular roles in the fibrogenic response. In this review, we cover the main metabolic reprogramming outcomes in renal fibrosis and provide a future perspective on the field of renal fibrometabolism.

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KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease

Cited by 142 publications

References 87 publications

KIM-1/TIM-1 is a Receptor for SARS-CoV-2 in Lung and Kidney

KIM-1/TIM-1 is a Receptor for SARS-CoV-2 in Lung and Kidney

Endothelial Dysfunction Accelerates Impairment of Mitochondrial Function in Ageing Kidneys via Inflammasome Activation

Metabolic reprogramming heterogeneity in chronic kidney disease

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