Protein-bound uremic toxins induce tissue remodeling by targeting the EGF receptor

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Indoxyl sulfate (IS) and p-cresol sulfate (PCS) are uremic toxins linked to kidney tissue remodeling.
• The precise molecular mechanisms by which IS and PCS induce kidney damage remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which IS and PCS induce kidney tissue remodeling.
• To investigate the role of the epidermal growth factor receptor (EGFR) in IS- and PCS-induced renal pathology.

Main Methods:

• Utilized cultured human proximal renal tubular cells and half-nephrectomized mice models.
• Employed molecular docking, in vitro spectrophotometry, and Western blotting to analyze EGFR activation and downstream signaling.
• Assessed the expression of matrix metalloproteinases (MMPs) 2 and 9.

Main Results:

• Molecular docking indicated IS and PCS bind to a pocket on the extracellular domain of EGFR.
• In vitro studies confirmed IS and PCS interact with EGFR, and in cultured cells, they activated EGFR signaling, leading to increased MMP-2 and MMP-9 expression.
• In vivo, IS and PCS treatment activated renal EGFR and elevated tubulointerstitial MMP-2 and MMP-9 levels.

Conclusions:

• IS and PCS may induce kidney tissue remodeling via direct binding and activation of the renal EGFR.
• EGFR activation by IS and PCS leads to downstream signaling that increases MMP expression, contributing to tissue remodeling.
• Targeting the EGFR pathway could be a potential therapeutic strategy for mitigating IS- and PCS-induced kidney damage.