Activated Alpha 2-Macroglobulin Is a Novel Mediator of Mesangial Cell Profibrotic Signaling in Diabetic Kidney Disease

Jackie Trinck, Renzhong Li, Yaseelan Palarasah, Stéphan Troyanov, Thomas Emil Andersen, Johannes Jakobsen Sidelmann, Mark D Inman, Salvatore V Pizzo, Bo Gao , Joan C Krepinsky*

*Kontaktforfatter for dette arbejde

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Abstrakt

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 targe
OriginalsprogEngelsk
Artikelnummer1112
TidsskriftBiomedicines
Vol/bind9
Udgave nummer9
Antal sider18
ISSN2227-9059
DOI
StatusUdgivet - sep. 2021

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