Combined saline and vildagliptin induced M2 macrophage polarization in hepatic injury induced by acute kidney injury

Abstract

Acute kidney injury (AKI) is a prevalent medical condition accompanied by mutual affection of other organs, including the liver resulting in complicated multiorgan malfunction. Macrophages play a vital role during tissue injury and healing; they are categorized into “classically activated macrophages” (M1) and “alternatively activated macrophages” (M2). The present study investigated and compared the conventional fluid therapy vs Dipeptidyl peptidase 4 inhibitor (DPP-4i) vildagliptin on the liver injury induced by AKI and evaluated the possible molecular mechanisms. Thirty rats comprised five groups (n = 6 rats/group): control, AKI, AKI+saline (received 1.5 mL of normal saline subcutaneous injection), AKI+vildagliptin (treated with oral vildagliptin 10 mg/kg), AKI+saline+vildagliptin. AKI was induced by intramuscular (i.m) injection of 50% glycerol (5 ml/kg). At the end of the work, we collected serum and liver samples for measurements of serum creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrotic factor-α (TNF-α), and interleukin-10 (IL-10). Liver samples were processed for assessment of inducible nitric oxide synthase (iNOS) as a marker for M1, arginase 1 (Arg-1) as an M2 marker, c-fos, c-Jun, mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1), and high-mobility-group-box1 (HMGB1) protein. The difference was insignificant regarding the relative expression of AP-1, c-Jun, c-fos, MAPK, and HMGB between the AKI+saline group and the AKI+Vildagliptin group. The difference between the same two groups concerning the hepatic content of the M1 marker (iNOS) and the M2 marker Arg-1 was insignificant. However, combined therapy produced more pronounced changes in these markers, as the difference in their relative expression between the AKI+saline+Vildagliptin group and both the AKI+saline group and the AKI+Vildagliptin group was significant. Accordingly, we suggest that the combined saline and vildagliptin hepatoprotective effect involves the downregulation of the MAPK/AP-1 signaling pathway.

Prolonged warm ischemia time increases mitogen-activated protein kinase activity and decreases perfusate cytokine levels in ex vivo rat liver machine perfusion

“…α-GST is a specific marker for hepatocellular damage, particularly effective in early detection ( 32 ). ARG1 is a marker of alternative activated (anti-inflammatory) macrophage ( 33 , 34 ).…”

Cardamonin mitigates kidney injury by modulating inflammation, oxidative stress, and apoptotic signaling in rats subjected to renal ischemia and reperfusion

“…Following IRI, inflammatory-associated biomarkers such as nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) are activated in the kidneys, leading to tissue damage characterized by endothelial and tubular cell dysfunction [ 4 ]. Both IL-1β and TNF-α, key proinflammatory cytokines, are released in response to IRI and regulate and modulate inflammation [ 5 ]. During the reperfusion phase, there is an infiltration of neutrophil cells, excessive production of TNF-α and IL-1β, and activation of NF-κB in renal tissues, suggesting a link between these factors in mediating IRI [ 6 ].…”