Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury
Conrad A. Farrar, David Tran, Ke Li, Weiju Wu, Qi Peng, Wilhelm Schwaeble, Wuding Zhou, Steven H. Sacks
Conrad A. Farrar, David Tran, Ke Li, Weiju Wu, Qi Peng, Wilhelm Schwaeble, Wuding Zhou, Steven H. Sacks
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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 2

Impact of CL-11 on renal injury induced by 50 minutes of ischemia.

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Impact of CL-11 on renal injury induced by 50 minutes of ischemia. Renal...
Renal injury and complement activation in Colec11+/+ and Colec11–/– mice following 50 minutes of ischemia and 24 hours of reperfusion. (A) Representative images of PAS staining of kidney sections from Colec11+/+ and Colec11–/– mice (n = 10 mice/group). Arrow indicates necrotic area of renal tubules seen in a longitudinal section at the junction of the renal cortex and medulla. 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 = 4 mice/group). (D) Quantification of neutrophils in kidney sections from the mice 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 G. (I) Representative images of immunofluorescence staining of C3d in kidney sections from Colec11+/+ and Colec11–/– mice (n = 10 mice/group). Scale bars: 25 μm. (J) Quantification of C3d in kidney sections from the mice represented in I. (K) BUN levels in Colec11+/+ and Colec11–/– mice after reperfusion (n = 10 mice/group). Dashed line represents the BUN baseline in normal, nonmanipulated mice. (B, D, F, H, J, and K) Each dot represents an individual mouse. *P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.001, by unpaired, 2-tailed Student’s t test.