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

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.

Uromodulin deficiency alters tubular injury and interstitial inflammation but not fibrosis in experimental obstructive nephropathy

“…; Yin et al. ). KIM‐1 protein levels were significantly up‐regulated in the UUO kidneys at all time‐points (days 7, 14, and 21), and KIM‐1 levels were significantly and remarkably higher in the UMOD−/− groups compared to the UMOD+/+ groups (4.3–13.7x) (Fig.…”

“…Beyond its proven value as tubular injury biomarker in numerous animal models and human kidney diseases, both acute and chronic (Yin et al. ), there is growing evidence that KIM‐1 serves a variety of functions that may either enhance or attenuate kidney injury, depending upon the context within which it is expressed (Humphreys et al. ; Yang et al.…”

“…In the UUO model, 90-100% of proximal tubules have been reported to express KIM-1 (Humphreys et al 2013). Beyond its proven value as tubular injury biomarker in numerous animal models and human kidney diseases, both acute and chronic (Yin et al 2016), there is growing evidence that KIM-1 serves a variety of functions that may either enhance or attenuate kidney injury, depending KIM-1 protein levels were significantly up-regulated in the UUO kidneys at all time-points (days 7, 14, and 21), and KIM-1 levels were significantly and remarkably higher in the UMODÀ/À groups compared to the UMOD+/+ groups (4.3-13.7x) ( Fig. 3A and B).…”

The role of phosphatidylserine recognition receptors in multiple biological functions

“…It is a proximal tubular cell (PTC) surface protein which is expressed in a wide range of kidney diseases. Upon PS recognition [83] it mediates the conversion of tubular epithelial cells into non-professional phagocytes [84], thereby promoting efferocytosis of apoptotic cells and exerting a protective effect against acute kidney injury [85][86][87][88][89][90]. However, KIM-1 binding to PS exerts nephroprotective action also through efferocytosis-independent mechanisms, that is, the limitation of renal epithelial cell damage through the inhibition of Gα12 [91] or the promotion of tubular epithelium repair through activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein (MAP) kinase (MAPK) signaling pathway [92].…”

Acute kidney injury and chronic kidney disease: From the laboratory to the clinic

“…If expression of KIM-1 continues chronically it is possible that this results in progressive uptake of noxious compounds from the intratubular lumen and secondary cell injury over time with senescence, secretion of proinflammatory and profibrotic cytokines. A transgenic mouse expressing KIM-1 developed CKD (85) and zebrafish overexpressing KIM-1 have smaller kidneys and higher mortality rates (86). …”