PUBLICATION
Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model
- Authors
- Yin, W., Naini, S.M., Chen, G., Hentschel, D.M., Humphreys, B.D., Bonventre, J.V.
- ID
- ZDB-PUB-151106-6
- Date
- 2016
- Source
- Journal of the American Society of Nephrology : JASN 27(7): 1943-57 (Journal)
- Registered Authors
- Bonventre, Joseph V., Hentschel, Dirk, Naini, Said Movahedi, Yin, Wenqing
- Keywords
- acute renal failure, chronic kidney disease, nephrotoxicity
- MeSH Terms
-
- Animals
- Disease Models, Animal
- Hepatitis A Virus Cellular Receptor 1/physiology*
- Kidney Diseases/etiology*
- Kidney Tubules*
- Mice
- TOR Serine-Threonine Kinases/physiology*
- PubMed
- 26538632 Full text @ J. Am. Soc. Nephrol.
Citation
Yin, W., Naini, S.M., Chen, G., Hentschel, D.M., Humphreys, B.D., Bonventre, J.V. (2016) Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model. Journal of the American Society of Nephrology : JASN. 27(7):1943-57.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping