Inhibition of cell surface GRP78 and activated α2M interaction attenuates kidney fibrosis

Area of Science:

• Nephrology
• Cell Biology
• Molecular Medicine

Background:

• Endoplasmic reticulum protein GRP78 (glycoprotein 78) translocates to the cell surface when bound by activated α2M (alpha-2-macroglobulin).
• This cell surface GRP78/α2M complex plays a role in glomerulosclerosis by inducing pro-fibrotic responses in mesangial cells.
• Interstitial fibrosis, a key factor in kidney disease progression, involves proximal tubular epithelial cells (PTEC) and renal fibroblasts.

Purpose of the Study:

• To investigate the role of cell surface GRP78 (csGRP78)/α2M complex in mediating interstitial fibrosis.
• To explore potential therapeutic interventions targeting the csGRP78/α2M interaction for kidney fibrosis.

Main Methods:

• Assessed csGRP78 and α2M levels in PTEC and renal fibroblasts under high glucose and TGF-β1 stimulation.
• Utilized neutralizing antibodies (C38 for csGRP78, Fα2M for α2M*) and an inhibitory peptide in mouse models of diabetic kidney disease (Akita mice) and non-diabetic kidney injury (unilateral ureteral obstruction).
• Evaluated the impact of these interventions on fibrotic protein production and signaling pathways (YAP/TAZ, Smad3).

Main Results:

• High glucose and TGF-β1 increased csGRP78 and α2M in PTEC and renal fibroblasts, and their inhibition reduced fibrotic protein production.
• TGF-β1-induced fibrosis was mediated by noncanonical YAP/TAZ signaling, not Smad3.
• In vivo inhibition of csGRP78/α2M interaction using antibodies or peptides significantly attenuated tubulointerstitial fibrosis and pro-fibrotic signaling in both diabetic and non-diabetic kidney disease models.

Conclusions:

• The csGRP78/α2M complex is a significant mediator of tubulointerstitial fibrosis in various kidney disease contexts.
• Targeting the csGRP78/α2M interaction represents a promising antifibrotic therapeutic strategy for kidney disease.