Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury
Conrad A. Farrar, … , Wuding Zhou, Steven H. Sacks
Conrad A. Farrar, … , Wuding Zhou, Steven H. Sacks
Published April 18, 2016
Citation Information: J Clin Invest. 2016;126(5):1911-1925. https://doi.org/10.1172/JCI83000.
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Research Article Nephrology

Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury

Abstract

Physiochemical stress induces tissue injury as a result of the detection of abnormal molecular patterns by sensory molecules of the innate immune system. Here, we have described how the recently discovered C-type lectin collectin-11 (CL-11, also known as CL-K1 and encoded by COLEC11) recognizes an abnormal pattern of L-fucose on postischemic renal tubule cells and activates a destructive inflammatory response. We found that intrarenal expression of CL-11 rapidly increases in the postischemic period and colocalizes with complement deposited along the basolateral surface of the proximal renal tubule in association with L-fucose, the potential binding ligand for CL-11. Mice with either generalized or kidney-specific deficiency of CL-11 were strongly protected against loss of renal function and tubule injury due to reduced complement deposition. Ex vivo renal tubule cells showed a marked capacity for CL-11 binding that was induced by cell stress under hypoxic or hypothermic conditions and prevented by specific removal of L-fucose. Further analysis revealed that cell-bound CL-11 required the lectin complement pathway–associated protease MASP-2 to trigger complement deposition. Given these results, we conclude that lectin complement pathway activation triggered by ligand–CL-11 interaction in postischemic tissue is a potent source of acute kidney injury and is amenable to sugar-specific blockade.

Authors

Conrad A. Farrar, David Tran, Ke Li, Weiju Wu, Qi Peng, Wilhelm Schwaeble, Wuding Zhou, Steven H. Sacks

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Figure 5

Renal tubule cell stress mediates CL-11 expression.

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Renal tubule cell stress mediates CL-11 expression. (A) Representative i...
(A) Representative immunofluorescence images of intracellular CL-11 in nonstressed and hypoxia-stressed RTECs or in hypothermia-stressed Colec11+/+ RTECs (permeabilized). CL-11 (red) and nuclei (blue) are shown. Scale bars: 10 μm. (B) Quantification of intracellular CL-11 in the RTECs shown in A. Data shown are from 6 individual images and representative of 4 independent experiments. (C) Relative Colec11 mRNA levels in nonstressed and hypothermia-stressed Colec11+/+ RTECs, as determined by qRT-PCR (n = 3). Data are representative of 2 experiments. *P < 0.05, by unpaired, 2-tailed Student’s t test. (D) Confocal microscopic image of CL-11 in hypothermia-stressed Colec11+/+ RTECs (nonpermeabilized). CL-11 (green), F-actin (red), and nuclei (blue) are shown. Views in the bottom and side panels show that CL-11 was present at the basal cell surface. (E) Representative immunofluorescence images of bound CL-11 in Colec11–/– RTECs that had been hypoxia stressed and then incubated with supernatants from nonstressed (Nonstressed sup) or hypoxia-stressed (Stressed sup) Colec11+/+ RTEC cultures or nonstressed Colec11–/– RTEC cultures (negative control), demonstrating that the supernatants from Colec11+/+ RTEC cultures had CL-11–binding activity. Scale bars: 25 μm. (F) Quantification of bound CL-11 in the RTECs represented in E. Data shown are from 7 individual images and representative of 2 independent experiments. (B and F) ****P < 0.001, by 1-way ANOVA.