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Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Characterized by overproduction and accumulation of extracellular matrix (ECM) proteins, glomerular sclerosis is its earliest manifestation. High glucose (HG) plays a central role by increasing matrix production by glomerular mesangial cells (MC). We previously showed that HG induces translocation of GRP78 from the endoplasmic reticulum to the cell surface (csGRP78), where it acts as a signaling molecule to promote intracellular profibrotic FAK/Akt activation. Here, we identify integrin β1 as a key transmembrane signaling partner for csGRP78. We show that it is required for csGRP78-regulated FAK/Akt activation in response to HG, as well as downstream production, secretion and activity of the well characterized profibrotic cytokine transforming growth factor β1 (TGFβ1). Intriguingly, integrin β1 also itself promotes csGRP78 translocation. Furthermore, integrin β1 effects on cytoskeletal organization are not required for its function in csGRP78 translocation and signaling. These data together support an important pathologic role for csGRP78/integrin β1 in mediating key profibrotic responses to HG in kidney cells. Inhibition of their interaction will be further evaluated as a therapeutic target to limit fibrosis progression in DKD.

Integrin β1/Cell Surface GRP78 Complex Regulates TGFβ1 and Its Profibrotic Effects in Response to High Glucose