Spleen Tyrosine Kinase Signaling Promotes Myeloid Cell Recruitment and Kidney Damage after Renal Ischemia/Reperfusion Injury

Abstract

Ischemia/reperfusion (I/R) injury is an important cause of acute and chronic renal failure. Neutrophils and macrophages, by integrin-based recruitment, play a key role in renal I/R injury. Integrin-based activation of spleen tyrosine kinase (Syk) contributes to myeloid cell adhesion to activated endothelial cells in vitro; however, whether Syk is required for myeloid cell recruitment and tubular damage in I/R injury is unknown. Therefore, we investigated the function of Syk in mouse I/R injury using two different approaches. C57Bl/6J mice underwent bilateral warm ischemia and were sacrificed after 30 minutes or 24 hours of reperfusion. Mice were treated with the Syk inhibitor CC0417, or vehicle, beginning 1 hour before surgery. Syk was expressed by infiltrating neutrophils, macrophages, and platelets in vehicle-treated I/R injury which exhibited severe renal failure and tubular damage at 24 hours. CC0417 treatment markedly reduced neutrophil, macrophage, and platelet accumulation with improved renal function and reduced tubular damage. Next, we compared mice with conditional Syk gene deletion in myeloid cells (Syk(My)) versus Syk(f/f) littermate controls in a 24-hour study. Syk(My) mice also showed a marked reduction in neutrophil and macrophage infiltration with significant protection from I/R-induced acute renal failure and tubular damage. These studies define a pathologic role for myeloid Syk signaling in renal I/R injury and identify Syk as a potential therapeutic target in this condition.

Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis

“…GS-642362 treatment dramatically reduced neutrophil infiltration into the kidney following IRI. This may reflect a reduction in the release of DAMPs as a result of reduced tubular cell damage, thereby reducing the recruitment and activation of neutrophils, which contribute to a "second wave" of tubular cell death in models of renal IRI [30][31][32]. Extracellular CypB can induce the chemotaxis of inflammatory cells into damaged tissues [33], although no studies of CypB−/− mice in IRI models have been reported.…”

“…Bilateral IRI surgery was performed in groups of 10 male C57BL6/J mice using ketamine and xylazine anesthesia as previously described [31]. A heating blanket connected to a rectal thermometer was used to keep body temperature at 37 • C. Following a midline abdominal incision, non-traumatic vascular clamps were used to clamp both renal pedicles for 17 min after which clamps were removed kidney reperfusion checked visually.…”

JUN Amino-Terminal Kinase 1 Signaling in the Proximal Tubule Causes Cell Death and Acute Renal Failure in Rat and Mouse Models of Renal Ischemia/Reperfusion Injury

“…Rats underwent bilateral IRI, as previously described. 14,15 Male rats were anesthetized with ketamine and xylazine. A heating blanket connected to a rectal thermometer was used to maintain body temperature at 37 C. Following a midline abdominal incision, both renal pedicles were clamped using non-traumatic vascular clamps for 25 minutes, during which the abdomen was temporarily sutured.…”

Cyclophilin A Promotes Inflammation in Acute Kidney Injury but Not in Renal Fibrosis

“…Neutrophil infiltration is a prominent response to renal IRI and plays a significant role in the induction of tubular necrosis [23][24][25]. In this study, WT mice exhibited a marked neutrophil infiltrate in the area of tubular damage (Figure 3A,B).…”