Kidney Injury Molecule-1 Protects against Gα12 Activation and Tissue Damage in Renal Ischemia-Reperfusion Injury

Ismail, Ola Z.; Zhang, Xizhong; Wei, Junjun; Haig, Aaron; Denker, Bradley M.; Suri, Rita S.; Şener, Alp; Gunaratnam, Lakshman

doi:10.1016/j.ajpath.2015.02.003

Cited by 48 publications

(62 citation statements)

References 29 publications

(46 reference statements)

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“…The results of our previous meta-analysis indicated that urinary KIM-1 was an efficient novel urinary biomarker for the diagnosis of AKI [8]. Ismail et al [27] reported that KIM-1 provided endogenous protection against renal ischaemia-reperfusion injury by inhibiting G proteinα12. However, these studies focused mainly on the expression and function of KIM-1 at certain disease stages.…”

Section: Discussionmentioning

confidence: 99%

Kidney Injury Molecule-1 is Elevated in Nephropathy and Mediates Macrophage Activation via the Mapk Signalling Pathway

Tian¹,

Shao²,

Xie³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Kidney injury molecule-1 (KIM-1) is highly expressed in renal tubular cells after injury and is usually regarded as an early biomarker of acute kidney injury(AKI). The aim of this study was to determine the role of KIM-1 in the development of renal tubular injury Methods: Clinical samples, three different animal models and in vitro experiments were utilized to determine the possible mechanism underlying the involvement of KIM-1 in kidney injury. Results: Both plasma and urinary KIM-1 expression levels were significantly higher in AKI and chronic kidney disease (CKD) patients than in healthy volunteers, and urinary KIM-1 expression was significantly higher in CKD patients than in AKI patients. According to the results of our research involving three different mouse models, KIM-1 expression was significantly increased during the early stage of kidney injury and was persistently elevated in renal fibrosis. Our immunofluorescence staining results indicated that KIM-1-positive tubules were surrounded by macrophage infiltrates in regions of kidney injury. Moreover, our transwell, western blotting and real-time PCR data showed that macrophage migration and phenotype transitions were mediated by KIM-1 through the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway inhibition could significantly reverse the effects of KIM-1 with respect to these macrophage phenotype changes and migration. Conclusions: KIM-1 expression was markedly elevated in both acute and chronic kidney injury and may play a pivotal role in macrophage activation via the MAPK pathway in kidney disease.

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Section: Discussionmentioning

confidence: 99%

Kidney Injury Molecule-1 is Elevated in Nephropathy and Mediates Macrophage Activation via the Mapk Signalling Pathway

Tian¹,

Shao²,

Xie³

et al. 2017

Cell Physiol Biochem

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“…Using the Sox9 driven Cre-ER 2 model crossed with R26R-tdTomato, Kumar et al showed that PT cells that initiated de novo expression of Sox9 after injury, contributed the most to repair, further implicating dedifferentiation as the predominant mechanism of epithelial repair [7]. Additionally, both PT-specific deletion of Sox9 in repair, and global deletion of Kim-1 during injury, exacerbated injury and delayed repair [7–9]. …”

Section: Tubular Injury and Repairmentioning

confidence: 99%

Fibrotic Changes Mediating Acute Kidney Injury to Chronic Kidney Disease Transition

hAinmhire

Humphreys²

2017

Nephron

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End-stage renal disease (ESRD) is common, costly, and it results from progressive chronic kidney disease (CKD). ESRD claims many lives every year. It is increasingly recognized that episodes of acute kidney injury (AKI) predispose to the future development of CKD and ESRD. While our understanding of the pathophysiology of the AKI to CKD transition is improving, there are no validated therapeutic strategies to prevent this transition. In this review, we summarize the recent progress made in defining the cellular and molecular events underlying the AKI to CKD transition and highlight potential therapeutic targets and strategies to reduce the incidence of CKD following AKI.

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“…[17][18][19] It is important to note that primary PTECs are entirely dependent on KIM-1 for efferocytosis. 20 Work by our group and that of Bonventre confirmed that, compared to wild-type mice, both KIM-1-deficient mice 20 and mice expressing a mucin domain deletion (mutant) 21 are more prone to ischemic acute kidney injury owing to 2 major mechanisms trig- 18 KIM-1 expression, or lack thereof, likely does not contribute to renal pathology in native conditions, as no differences in kidney function or pathology between wild-type and KIM-1-deficient mice were observed prior to IRI induction.…”

Section: Introductionmentioning

confidence: 99%

Donor kidney injury molecule-1 promotes graft recovery by regulating systemic necroinflammation

Lee

Ismail

Zhang

et al. 2018

American Journal of Transplantation

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Ischemia-reperfusion injury during kidney transplantation predisposes to delayed graft function, rejection, and premature graft failure. Exacerbation of tissue damage and alloimmune responses may be explained by necroinflammation: an autoamplification loop of cell death and inflammation, which is mediated by the release of damage-associated molecular patterns (eg, high-mobility group box-1; HMGB1) from necrotic cells that activate both innate and adaptive immune pathways. Kidney injury molecule-1 (KIM-1) is a phosphatidylserine receptor that is upregulated on injured proximal tubular epithelial cells and enables them to clear apoptotic and necrotic cells. Here we show a pivotal role for clearance of dying cells in regulating necroinflammation in a syngeneic murine kidney transplant model. We found persistent KIM-1 expression in KIM-1 kidney grafts posttransplantation. Compared to recipients of KIM-1 kidneys, recipients of KIM-1 kidneys exhibited significantly more renal dysfunction, apoptosis and necrosis, tubular obstruction, and graft failure. KIM-1 grafts also had more inflammatory cytokines, infiltrating neutrophils, and macrophages compared to KIM-1 grafts. Most significantly, passive release of HMGB1 from apoptotic and necrotic cells led to dramatically higher serum HMGB1 levels and increased proinflammatory macrophages in recipients of KIM-1 grafts. Our data identify an endogenous protective mechanism against necroinflammation in kidney grafts that may be of therapeutic relevance in transplantation.

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Kidney Injury Molecule-1 Protects against Gα12 Activation and Tissue Damage in Renal Ischemia-Reperfusion Injury

Cited by 48 publications

References 29 publications

Kidney Injury Molecule-1 is Elevated in Nephropathy and Mediates Macrophage Activation via the Mapk Signalling Pathway

Kidney Injury Molecule-1 is Elevated in Nephropathy and Mediates Macrophage Activation via the Mapk Signalling Pathway

Fibrotic Changes Mediating Acute Kidney Injury to Chronic Kidney Disease Transition

Donor kidney injury molecule-1 promotes graft recovery by regulating systemic necroinflammation

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