Protection against Renal Ischemia Reperfusion Injury by CD44 Disruption

Abstract

Inflammation contributes to renal ischemia reperfusion (I/R) injury, potentially causing renal dysfunction. The inflammatory infiltrate mainly consists of neutrophils, which are deleterious for the renal tissue. Because CD44 is expressed by neutrophils and is rapidly upregulated by capillary endothelial cells after I/R injury, it was hypothesized that CD44 might play an important role in the development of I/R injury. This study showed that rapid CD44 upregulation on renal capillary endothelial cells mediates neutrophil recruitment to the postischemic tissue. Hence, CD44 deficiency led to decreased influx of neutrophils regardless of comparable levels in chemotactic factors expressed in the kidney. The reduced influx of neutrophils was associated with preserved renal function and morphology. Adoptive transfer experiments of labeled neutrophils revealed that endothelial CD44 rather than neutrophil CD44 mediates neutrophil migration. Activation of neutrophils increased cell-surface expression of hyaluronic acid (HA). Altogether, a novel mechanism in the recruitment of neutrophils that involves interaction of endothelial CD44 and neutrophil HA was found. Either blocking endothelial CD44 or removal of neutrophil HA decreased rolling and adhesion of neutrophils. Administration of anti-CD44 to mice reduced the influx of neutrophils into the postischemic tissue, associated with renal function preservation. Therefore, anti-CD44 -based therapies may contribute to prevent or reduce renal I/R injury.

The role of CD44 in the acute and resolution phase of the host response during pneumococcal pneumonia

“…[8][9][10]24,25 In light of the important role of neutrophils and macrophages in host defense in pneumococcal pneumonia, 3 we determined the cellular composition of BALF harvested at 6, 24 or 48 h after infection with a lethal dose of S. pneumoniae (10 4 CFU). Whereas, macrophage numbers were similar in BALF harvested from CD44 KO and WT mice at all time points (data not shown), neutrophil counts were slightly enhanced at 6 h and more clearly at 24 h after infection, although these differences did not reach statistical significance (P ¼ 0.16 and P ¼ 0.06, respectively; Figure 3a).…”

“…Several studies have shown a positive role of CD44 in inflammatory cell recruitment, 10,25,[36][37][38][39][40][41] whereas other investigations reported enhanced inflammatory cell migration in the absence of CD44. 8,9,24,35 This discrepancy is probably because of the differences in the cell type studied, the stimulus and organ involved, and the severity of the insult.…”

“…[5][6][7] In accordance, CD44 has been shown to have an eminent role in the (sub)acute inflammatory response to both infectious and sterile stimuli. [8][9][10][11] CD44 is also involved in the resolution of inflammation, as demonstrated by in vivo models of non-infectious lung injury induced by bleomycin or lipopolysaccharide (LPS); in these studies CD44 deficiency resulted in prolonged accumulation of inflammatory cells and a persistent rise in the levels of the main CD44 ligand hyaluronic acid (HA). 8,12 Furthermore, during infection, CD44 may influence host defense by affecting phagocytosis.…”

RAGE Does Not Contribute to Renal Injury and Damage upon Ischemia/Reperfusion-Induced Injury

“…Renal I/R injury was induced as described previously [15][16][17] . Briefly, both renal arteries were clamped for 30 min under general anesthesia (0.07 ml/10 g mouse of fentanyl citrate fluanisone midazolam mixture containing: 1.25 mg/ml midazolam (Roche Diagnostics Corp.), 0.08 mg/ml fentanyl citrate, and 2.5 mg/ml fluanisone (Janssen Pharmaceutica)), which induces profound renal damage and dysfunction without inducing mortality [17] .…”

“…Renal function and tubular damage was determined as described previously [15,16] . The degree of tubular damage was assessed on periodic acid-Schiff diastase (PASD)-stained paraffinembedded tissue sections.…”