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

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...

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Bibliographic Details
Published in:Journal of the American Society of Nephrology 2015-02, Vol.26 (2), p.281-290
Main Authors: Sun, Chiao-Yin, Young, Guang-Huar, Hsieh, Yu-Ting, Chen, Yau-Hung, Wu, Mai-Szu, Wu, Vin-Cent, Lee, Jia-Hung, Lee, Chin-Chan
Format: Article
Language:English
Subjects:
Animals
Brief Communications
Cells, Cultured
Cresols - administration & dosage
Cresols - pharmacology
Humans
In Vitro Techniques
Indican - administration & dosage
Indican - pharmacology
Injections, Intraperitoneal
Kidney - drug effects
Kidney - pathology
Kidney - surgery
Kidney Tubules, Proximal - drug effects
Kidney Tubules, Proximal - metabolism
Kidney Tubules, Proximal - pathology
Matrix Metalloproteinase 2 - metabolism
Matrix Metalloproteinase 9 - metabolism
Mice
Mice, Inbred Strains
Models, Animal
Nephrectomy
Receptor, Epidermal Growth Factor - drug effects
Signal Transduction - drug effects
Toxins, Biological - administration & dosage
Toxins, Biological - pharmacology
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Summary: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.
ISSN:1046-6673
1533-3450
DOI:10.1681/asn.2014010021