Abstract
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.
Highlights
While best studied in tumor cells, we recently showed that cell surface translocation of GRP78 (csGRP78) is increased by high glucose (HG) in mesangial cells (MCs) and in diabetic kidneys and showed its importance in mediating HG-induced profibrotic responses through PI3K/Akt signaling [7]
We studied the relationship between urinary α2M* and TGFβ1 using samples from a published cohort of type 2 diabetic patients with overt Diabetic kidney disease (DKD) who previously participated in a longitudinal biomarker study [25]
We recently demonstrated that csGRP78 is increased in diabetic kidneys and showed its importance in mediating MC HG-induced profibrotic signaling [7]
Summary
While best studied in tumor cells, we recently showed that csGRP78 is increased by HG in MCs and in diabetic kidneys and showed its importance in mediating HG-induced profibrotic responses through PI3K/Akt signaling [7]. The resulting complex is considered the activated form of α2M, designated α2M*, in which receptor recognition sites are exposed This allows interaction with its two identified receptors, low-density lipoprotein receptor-related protein (LRP1) and csGRP78. Α2M* binds to a region in the NH2 -terminal domain of csGRP78 to initiate signaling pathways that promote tumor cell proliferation and survival such as ERK1/2, p38 MAPK, PI3K/Akt, and NF-κB [11,13,14,15,16]. Whether α2M is activated in DKD and plays a role in its pathophysiology is unknown and is the focus of this study
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