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

Chiao Yin Sun, Guang Huar Young, Yu Ting Hsieh, Yau Hung Chen, Mai Szu Wu, Vin Cent Wu, Jia Hung Lee, Chin Chan Lee

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Indoxyl sulfate and p-cresol sulfate have been suggested to induce kidney tissue remodeling. This study aimed to clarify the molecular mechanisms underlying this tissue remodeling using cultured human proximal renal tubular cells and half-nephrectomized mice treated with indoxyl sulfate or p-cresol sulfate as study models. Molecular docking results suggested that indoxyl sulfate and p-cresol sulfate dock on a putative interdomain pocket of the extracellular EGF receptor. In vitro spectrophotometric analysis revealed that the presence of a synthetic EGF receptor peptide significantly decreased the spectrophotometric absorption of indoxyl sulfate and p-cresol sulfate. In cultured cells, indoxyl sulfate and p-cresol sulfate activated the EGF receptor and downstream signaling by enhancing receptor dimerization, and increased expression of matrix metalloproteinases 2 and 9 in an EGF receptor-dependent manner. Treatment of mice with indoxyl sulfate or p-cresol sulfate significantly activated the renal EGF receptor and increased the tubulointerstitial expression of matrix metalloproteinases 2 and 9. In conclusion, indoxyl sulfate and p-cresol sulfate may induce kidney tissue remodeling through direct binding and activation of the renal EGF receptor.

Original languageEnglish
Pages (from-to)281-290
Number of pages10
JournalJournal of the American Society of Nephrology
Volume26
Issue number2
DOIs
Publication statusPublished - Feb 1 2015

ASJC Scopus subject areas

  • Nephrology

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