KIM-1–mediated phagocytosis reduces acute injury to the kidney

Yang, Li; Brooks, Craig R.; Xiao, Sheng; Sabbisetti, Venkata; Yeung, Melissa Y.; Hsiao, Li‐Li; Ichimura, Takaharu; Kuchroo, Vijay K.; Bonventre, Joseph V.

doi:10.1172/jci75417

Cited by 275 publications

(275 citation statements)

References 51 publications

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“…36 Although temporary expression of KIM-1 after injury will help to eliminate the apoptotic cells and debris and partially restore renal function, persistent KIM-1 expression in renal epithelial cells induces inflammation, tubulointerstitial fibrosis, and a murine CKD phenotype. 37 Here, we have demonstrated that persistent expression of Kim-1 in zebrafish tubular epithelial cells results in the development of pericardial edema, reduced GFR, tubular damage, and a higher mortality. The damaged pronephric tubules were marked with flattening and loss of tubular brush border and atrophic tubular epithelial cells with accumulation of vacuoles.…”

Section: Discussionmentioning

confidence: 76%

“…42 Recently, we demonstrated that Kim-1 interaction with p85 and subsequent PI3K-dependent signaling pathway play an important role in kidney injury and repair. 37,43 The PI3K/AKT/mTOR pathway is a well known intracellular signaling pathway related to cell growth, proliferation, and survival. 44,45 Thus, it is likely Kim-1 directly binds to p85 and regulates mTOR activity through the AKT signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

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Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model

Yin¹,

Naini²,

Chen³

et al. 2015

JASN

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Kidney injury molecule 1 (KIM-1), an epithelial phagocytic receptor, is markedly upregulated in the proximal tubule in various forms of acute and chronic kidney injury in humans and many other species. Whereas acute expression of KIM-1 has adaptive anti-inflammatory effects, chronic expression may be maladaptive in mice. Here, we characterized the zebrafish Kim family, consisting of Kim-1, Kim-3, and Kim-4. Kim-1 was markedly upregulated in kidney after gentamicin-induced injury and had conserved phagocytic activity in zebrafish. Both constitutive and tamoxifen-induced expression of Kim-1 in zebrafish kidney tubules resulted in loss of the tubule brush border, reduced GFR, pericardial edema, and increased mortality. Kim-1-induced kidney injury was associated with reduction of growth of adult fish. Kim-1 expression led to activation of the mammalian target of rapamycin (mTOR) pathway, and inhibition of this pathway with rapamycin increased survival. mTOR pathway inhibition in KIM-1-overexpressing transgenic mice also significantly ameliorated serum creatinine level, proteinuria, tubular injury, and kidney inflammation. In conclusion, persistent Kim-1 expression results in chronic kidney damage in zebrafish through a mechanism involving mTOR. This observation predicted the role of the mTOR pathway and the therapeutic efficacy of mTOR-targeted agents in KIM-1-mediated kidney injury and fibrosis in mice, demonstrating the utility of the Kim-1 renal tubule zebrafish models.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model

Yin¹,

Naini²,

Chen³

et al. 2015

JASN

Self Cite

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“…TIM‐1 expressed on phagocytes is involved in the recognition of apoptotic cells and initiation of efferocytosis by interacting with phosphatidylserine expressing apoptotic cells 51. Mice expressing defective TIM‐1 fail to phagocytose apoptotic cells in acute renal injury consistent with the critical role of TIM‐1 in efferocytosis 52. Unlike 3B3 and 3D10 agonist antibody clones, RMT1‐10 does not block binding of phosphatidylserine‐expressing apoptotic cells to TIM‐1‐expressing phagocytes53 indicating a potential role of RMT1‐10 in facilitating efferocytosis.…”

Section: Discussionmentioning

confidence: 84%

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

Hosseini

Kanellakis

et al. 2018

JAHA

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BackgroundPeritoneal B1a cells attenuate atherosclerosis by secreting natural polyclonal immunoglobulin M (IgM). Regulatory B cells expressing T‐cell immunoglobulin mucin domain‐1 (TIM‐1) expanded through TIM‐1 ligation by anti‐TIM‐1 monoclonal antibody (RMT1‐10) induces immune tolerance.Methods and ResultsWe examined the capacity of RMT1‐10 to expand peritoneal B1a cells to prevent atherosclerosis development and retard progression of established atherosclerosis. RMT1‐10 treatment selectively doubled peritoneal B1a cells, tripled TIM‐1+ B1a cells and increased TIM‐1+IgM+interleukin (IL)‐10+ by 3‐fold and TIM‐1+IgM+IL‐10− B1a cells by 2.5‐fold. Similar expansion of B1a B cells was observed in spleens. These effects reduced atherosclerotic lesion size, increased plasma IgM and lesion IgM deposits, and decreased oxidatively modified low‐density lipoproteins in lesions. Lesion CD4+ and CD8+ T cells, macrophages and monocyte chemoattractant protein‐1, vascular cell adhesion molecule‐1, expression of proinflammatory cytokines monocyte chemoattractant protein‐1, vascular cell adhesion molecule‐1, IL1β, apoptotic cell numbers and necrotic cores were also reduced. RMT1‐10 treatment failed to expand peritoneal B1a cells and reduce atherosclerosis after splenectomy that reduces B1a cells, indicating that these effects are B1a cell‐dependent. Apolipoprotein E‐KO mice fed a high‐fat diet for 6 weeks before treatment with RMT1‐10 also increased TIM‐1+IgM+ IL‐10+ and TIM‐1+IgM+ IL‐10− B1a cells and IgM levels and attenuated progression of established atherosclerosis.Conclusions RMT1‐10 treatment attenuates atherosclerosis development and progression by selectively expanding IgM producing atheroprotective B1a cells. Antibody‐based in vivo expansion of B1a cells could be an attractive approach for treating atherosclerosis.

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“…21 In experimental AKI, KIM-1 protein regulates phagocytosis of damaged cells and thereby limits injury. 43 An extracellular domain of KIM-1 can be detected by enzyme linked immunosorbent assays and is useful as a urinary biomarker in patients with AKI. In a study of 40 children undergoing CPB, urinary KIM-1 levels were markedly increased in the children who developed AKI, with an AUC of 0.83 at 12 hours post-CPB for predicting AKI, indicating that it is a delayed biomarker of AKI compared to NGAL.…”

Section: Kidney Injury Molecule-1 (Kim-1)mentioning

confidence: 99%

Pediatric acute kidney injury: prevalence, impact and management challenges

Ciccia¹,

Devarajan²

2017

IJNRD

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Abstract:The incidence of pediatric acute kidney injury (AKI) is increasing globally, as are the associated morbidities and mortality. A recent standardization of the definition of AKI has allowed for a more accurate assessment of the epidemiology of pediatric AKI. Recent advances in leveraging electronic medical health record systems have allowed for real-time risk stratification and prevention of pediatric AKI in the hospital setting. Newly developed and validated clinical scores have improved our ability to predict AKI and provide a rational context for biomarker utilization in hospitalized children. Novel non-invasive diagnostic and predictive biomarkers have been launched globally to improve our ability to diagnose and predict AKI and its adverse outcomes as well as recovery. This review summarizes the most current literature, focusing on the epidemiology, management, and early diagnostic strategies in pediatric AKI.

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KIM-1–mediated phagocytosis reduces acute injury to the kidney

Cited by 275 publications

References 51 publications

Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model

Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

Pediatric acute kidney injury: prevalence, impact and management challenges

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