Activated Alpha 2-Macroglobulin Is a Novel Mediator of Mesangial Cell Profibrotic Signaling in Diabetic Kidney Disease.
Jackie TrinkRenzhong LiYaseelan PalarasahStéphan TroyanovThomas Emil AndersenJohannes J SidelmannMark D InmanSalvatore V PizzoBo GaoJoan C KrepinskyPublished in: Biomedicines (2021)
Diabetic kidney disease (DKD) is caused by the overproduction of extracellular matrix proteins (ECM) by glomerular mesangial cells (MCs). We previously showed that high glucose (HG) induces cell surface translocation of GRP78 (csGRP78), mediating PI3K/Akt activation and downstream ECM production. Activated alpha 2-macroglobulin (α2M*) is a ligand known to initiate this signaling cascade. Importantly, increased α2M was observed in diabetic patients' serum, saliva, and glomeruli. Primary MCs were used to assess HG responses. The role of α2M* was assessed using siRNA, a neutralizing antibody and inhibitory peptide. Kidneys from type 1 diabetic Akita and CD1 mice and human DKD patients were stained for α2M/α2M*. α2M transcript and protein were significantly increased with HG in vitro and in vivo in diabetic kidneys. A similar increase in α2M* was seen in media and kidneys, where it localized to the mesangium. No appreciable α2M* was seen in normal kidneys. Knockdown or neutralization of α2M/α2M* inhibited HG-induced profibrotic signaling (Akt activation) and matrix/cytokine upregulation (collagen IV, fibronectin, CTGF, and TGFβ1). In patients with established DKD, urinary α2M* and TGFβ1 levels were correlated. These data reveal an important role for α2M* in the pathogenesis of DKD and support further investigation as a potential novel therapeutic target.
Keyphrases
- high glucose
- endothelial cells
- extracellular matrix
- signaling pathway
- wound healing
- pi k akt
- type diabetes
- cell cycle arrest
- cell surface
- cell proliferation
- fluorescent probe
- induced apoptosis
- end stage renal disease
- single cell
- ejection fraction
- transforming growth factor
- living cells
- chronic kidney disease
- newly diagnosed
- cell death
- poor prognosis
- diabetic nephropathy
- drug delivery
- genome wide
- climate change
- dna methylation
- high fat diet induced
- patient reported outcomes
- cell therapy
- insulin resistance
- rna seq
- amino acid
- skeletal muscle
- binding protein