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

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.

SUBMITTER: Sun CY

PROVIDER: S-EPMC4310659 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Sun Chiao-Yin CY Young Guang-Huar GH Hsieh Yu-Ting YT Chen Yau-Hung YH Wu Mai-Szu MS Wu Vin-Cent VC Lee Jia-Hung JH Lee Chin-Chan CC

Journal of the American Society of Nephrology : JASN 20140710 2

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 spectrophotomet ...[more]

PMID: 25012179

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Project description:Background and objectivesCurrent hemodialysis techniques fail to efficiently remove the protein-bound uremic toxins p-cresyl sulfate and indoxyl sulfate due to their high degree of albumin binding. Ibuprofen, which shares the same primary albumin binding site with p-cresyl sulfate and indoxyl sulfate, can be infused during hemodialysis to displace these toxins, thereby augmenting their removal.Design, setting, participants, & measurementsWe infused 800 mg ibuprofen into the arterial bloodline between minutes 21 and 40 of a conventional 4-hour high-flux hemodialysis treatment. We measured arterial, venous, and dialysate outlet concentrations of indoxyl sulfate, p-cresyl sulfate, tryptophan, ibuprofen, urea, and creatinine before, during, and after the ibuprofen infusion. We report clearances of p-cresyl sulfate and indoxyl sulfate before and during ibuprofen infusion and dialysate concentrations of protein-bound uremic toxins normalized to each patient's average preinfusion concentrations.ResultsWe studied 18 patients on maintenance hemodialysis: age 36±11 years old, ten women, and mean vintage of 37±37 months. Compared with during the preinfusion period, the median (interquartile range) clearances of indoxyl sulfate and p-cresyl sulfate increased during ibuprofen infusion from 6.0 (6.5) to 20.2 (27.1) ml/min and from 4.4 (6.7) to 14.9 (27.1) ml/min (each P<0.001), respectively. Relative median (interquartile range) protein-bound uremic toxin dialysate outlet levels increased from preinfusion 1.0 (reference) to 2.4 (1.2) for indoxyl sulfate and to 2.4 (1.0) for p-cresyl sulfate (each P<0.001). Although median serum post- and predialyzer levels in the preinfusion period were similar, infusion led to a marked drop in serum postdialyzer levels for both indoxyl sulfate and p-cresyl sulfate (-1.0 and -0.3 mg/dl, respectively; each P<0.001). The removal of the nonprotein-bound solutes creatinine and urea was not increased by the ibuprofen infusion.ConclusionsInfusion of ibuprofen into the arterial bloodline during hemodialysis significantly increases the dialytic removal of indoxyl sulfate and p-cresyl sulfate and thereby, leads to greater reduction in their serum levels.

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

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

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