BAY61‐3606 protects kidney from acute ischemia/reperfusion injury through inhibiting spleen tyrosine kinase and suppressing inflammatory macrophage response

Abstract

Acute kidney injury (AKI) is a highly prevalent clinical syndrome with high mortality and morbidity. Previous studies indicated that inflammation promotes tubular damage and plays a key role in AKI progress. Spleen tyrosine kinase (Syk) has been linked to macrophage-related inflammation in AKI. Up to date, however, no Syk-targeted therapy for AKI has been reported. In this study, we employed both cell model of LPS-induced bone marrow-derived macrophage (BMDM) and mouse model of ischemia/reperfusion injury (IRI)-induced AKI to evaluate the effects of a Syk inhibitor, BAY61-3606 (BAY), on macrophage inflammation in vitro and protection of kidney from AKI in vivo. The expression and secretion of inflammatory cytokines, both in vitro and in vivo, were significantly inhibited even back to normal levels by BAY. The upregulated serum creatinine and blood urea nitrogen levels in the AKI mice were significantly reduced after administration of BAY, implicating a protective effect of BAY on kidneys against IRI. Further analyses from Western blot, immunofluorescence staining and flow cytometry revealed that BAY inhibited the Mincle/Syk/NF-κB signaling circuit and reduced the inflammatory response. BAY also inhibited the reactive oxygen species (ROS), which further decreased the Talents, Grant/Award Number: Lan HuiYao Team formation of inflammasome and suppressed the mature of IL-1β and IL-18. Notably, these inhibitory effects of BAY on inflammation and inflammasome in BMDM were significantly reversed by Mincle ligand, trehalose-6,6-dibehenate. In summary, these findings provided compelling evidence that BAY may be an efficient inhibitor of the Mincle/Syk/NF-κB signaling circuit and ROS-induced inflammasome, which may help to develop Syk-inhibitors as novel therapeutic agents for AKI.

Artesunate relieves acute kidney injury through inhibiting macrophagic Mincle‐mediated necroptosis and inflammation to tubular epithelial cell

“…A recent study demonstrated that Mincle is essential for maintaining the M1 phenotype of macrophage in kidney of AKI, and down‐regulation of Mincle in macrophage relieved the renal injury, suggesting that Mincle is a key promotor for macrophagic inflammation in AKI 20 . Our previous research also proved that inhibition of Mincle‐related signal pathway protects kidney from AKI injury 21 . Therefore, drug intervention targeting Mincle may be the key to the treatment of AKI.…”

“…Bone marrow–derived macrophages (BMDM) were isolated from the tibia and femur of C57BL/6 mice and differentiated in low‐glucose DMEM medium containing 30% supernatant of L929 cell for 7 days following the protocol in our previous study. 21 To obtain the primary tubular epithelial cells (mTEC) from mouse, the kidney was digested with 3 mg/ml Collagen 4 at 37℃ for 15min, then filtered the suspension on a 70‐μm cell strainer and centrifuged at 120 g for 5 min, followed by culturing the tubular epithelial cells in F12/DMEM medium with 5% foetal bovine serum containing 50 ng/ml epidermal growth factor and 5 μl/ml ITS‐G for 5 days. All cells were incubated in a 37℃ incubator containing a constant 5% CO 2 .…”

“… 20 Our previous research also proved that inhibition of Mincle‐related signal pathway protects kidney from AKI injury. 21 Therefore, drug intervention targeting Mincle may be the key to the treatment of AKI.…”

BAY61‑3606 attenuates neuroinflammation and neurofunctional damage by inhibiting microglial Mincle/Syk signaling response after traumatic brain injury

“…The incision was then sutured and the mice were placed on a 36-37°C heat pad. Mice in the TBI + BAY and BAY groups were administered with BAY (3 mg/kg) intraperitoneally ( 30 ) for 7 days after TBI insult. Mice in the BAY group did not receive CCI insult.…”

Alternative polyadenylation trans-factor FIP1 exacerbates UUO/IRI-induced kidney injury and contributes to AKI-CKD transition via ROS-NLRP3 axis

“…In kidney injury, oxidative stress and inflammation are the most significant characteristics, as well as pivotal pathological factors 4 . In response to injury, inflammation initially emerges as a reno-protective role.…”