Midkine promotes kidney injury in diabetic kidney disease by increasing neutrophil extracellular traps formation

Abstract

Background: We sought to investigate the role of midkine (MK) on neutrophil extracellular trap formation (NETosis) and diabetic kidney disease (DKD) progression. Methods: The expression of MK and NETosis in the renal tissue of DKD patients was examined by immunohistochemistry and immunofluorescence, respectively. Neutrophils extracted from mouse bone marrow by gradient centrifugation were treated with MK for this in-vitro study. A mouse diabetes model was induced by a high-fat diet combined with an intraperitoneal injection of streptozocin (STZ). Antisense oligodeoxynucleotide (ODN) for MK inhibition was administered via tail vein injection. Results: We found that the expression of MK was increased in the kidney tissue of DKD patients. Additionally, a greater number of neutrophils were primed toward NETosis in the kidney tissue of DKD patients, which was manifested by the increased expression of NETosis biomarkers citrullinated histone H3 (H3Cit) and myeloperoxidase (MPO). In vitro, MK treatment concentration-dependently increased neutrophil proliferation (cell counting kit-8). Further, western blot and enzyme-linked immunosorbent assays showed that MK (100 ng/mL) significantly promoted NETosis and the expression of inflammatory factors interleukin (IL)-1 and IL-6 secretion in high-glucose treated neutrophils. In the mouse diabetes model, MK promoted the pathological damage and fibrosis of kidney tissue, as demonstrated by the reversion of the pathological damage and fibrosis by the MK antisense ODN [diabetes mellitus (DM) + MK -ODN] treatment. Additionally, the inhibition of MK reduced the formation of NETs. Conclusions: MK promotes DKD progression by increasing NETosis.

Identification and analysis of chemokine-related and NETosis-related genes in acute pancreatitis to develop a predictive model

“…Prior studies have demonstrated that depleting or inhibiting neutrophils can protect against pancreatic tissue damage in inflammatory responses reliant on neutrophil activity ( Cui et al, 2017 ). Neutrophil-induced NETosis is a distinct form of neutrophil death that differs from apoptosis and necrosis and significantly contributes to tissue damage ( Liu et al, 2022 ; Wang C. L. et al, 2023 ). By responding to chemokines, activated neutrophils migrate into the site of inflammation, produce antimicrobial agents, and undergo NETosis ( Balachandran et al, 2022 ).…”

Nasopharynx Battlefield: Cellular Immune Responses Mediated by Midkine in Nasopharyngeal Carcinoma and COVID-19

“…In several inflammatory diseases, MK has been shown to exacerbate the condition through promoting NETosis, neutrophil trafficking, and macrophage accumulation [43,44,127,128]. Based on the findings discussed in the preceding section, it is reasonable to suggest that accelerated MK expression contributes to the recruitment of innate immune cells, which helps to modulate the immunopathology in COVID-19 patients.…”

Midkine promotes renal fibrosis by stabilizing C/EBPβ to facilitate endothelial-mesenchymal transition

“…Strong MDK expression was observed in patients with diabetic nephropathy 17 and other inflammatory conditions 18 , 19 . Liu et al reported that promoted expression of MDK accelerated the pathological damage and fibrosis in diabetic kidney diseases by increasing neutrophil extracellular trap 20 . Similarly, Misa et al found knockout of Mdk significantly ameliorated lung fibrosis with lower expression of both collagen and α-Smooth Muscle Actin (ACTA2) 21 .…”