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 3

Impact of CL-11 on injury induced by milder ischemic insult.

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Impact of CL-11 on injury induced by milder ischemic insult. Renal injur...
Renal injury is shown for Colec11+/+ and Colec11–/– mice following 30 minutes of ischemia and 24 hours of reperfusion. (A) Representative images of PAS staining of kidney sections from Colec11+/+ and Colec11–/– mice (n = 8 mice/group). Arrow indicates necrotic renal tubules seen in a longitudinal section at the corticomedullary junction. Scale bars: 100 μm. (B) Severity scores for renal tubular injury in the mice represented in A. (C) Representative images of immunochemical staining of neutrophils in kidney sections from Colec11+/+ and Colec11–/– mice (n = 3 mice/group). Scale bars, 100 μm. (D) Quantification of neutrophils in the kidney sections represented in C. (E) Representative images of immunochemical staining of leukocytes in kidney sections from Colec11+/+ and Colec11–/– mice (n = 3 mice/group). Scale bars: 100 μm. (F) Quantification of leukocytes in the kidney sections represented in E. (G) Representative images of immunochemical staining of macrophages in kidney sections from Colec11+/+ and Colec11–/– mice (n = 3 mice/group). Scale bars, 100 μm. (H) Quantification of macrophages in the kidney sections represented in panel G. (I) BUN levels in Colec11+/+ and Colec11–/– mice after reperfusion (n = 8 mice/group). Dashed line represents the BUN baseline in normal, nonmanipulated mice. (J) Representative immunofluorescence microscopic images of CL-11 (red) and C3d (green) and a merged image of CL-11 and C3d in ischemic kidney tissue. Scale bars: 25 μm. (K and L) Enlarged images (original magnification, ×400) of the merged image in J. Arrows indicate where the linear deposit of complement is dotted with CL-11 (orange) along the basolateral surface of the tubular epithelium, which is best appreciated at higher magnification. (B, D, F, H, and I) Each dot represents an individual mouse. *P < 0.05, ***P < 0.005, and ****P < 0.001, by unpaired, 2-tailed Student’s t test.