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Vascular smooth muscle cell (VSMC) proliferation is a key event in the progression of arteriosclerosis. Clinical studies show that uremic toxins deteriorate the arteriosclerosis in renal failure patients. Indoxyl sulfate (IS) is a strong protein-bound uremic toxin, but the effect of IS on VSMC proliferation has not been studied. We examined the effect of IS on rat VSMC proliferation, assessed by a cell counting kit (4-[3-[4-lodophenyl]-2-4(4-nitrophenyl)-2H-5-tetrazolio-1,3-benzene disulfonate] assay) and by [(3)H]thymidine incorporation in vitro. We further evaluated a contribution of mitogen-activated protein kinase (MAPK; p44/42 MAPK) to VSMC proliferation by IS. Immunohistochemical staining was performed for VSMCs using antirat organic anion transporter (OAT)3 antibody. The mRNA expressions of platelet-derived growth factor (PDGF)-A and -C chains, and PDGF-beta receptor were evaluated by real-time PCR. IS stimulated the proliferation of VSMCs in a concentration-dependent manner and activated p44/42 MAPK. Concentration of IS needed to stimulate the proliferation of rat VSMC was about 250 microM, which is compatible with that in the serum of end-stage renal failure patients. PD98059 (10 microM), a selective inhibitor of MAPK/extracellular signal-regulated kinase, inhibited the IS-induced (250 microM) VSMC proliferation and phosphorylation of MAPK. Probenecid (0.5 mM), an inhibitor and substrate of OAT, inhibited the IS-induced (250 microM) VSMC proliferation. Rat OAT3 was detected in VSMCs. The mRNA expressions of PDGF-C chain and PDGF-beta receptor were significantly increased by IS. We conclude that IS directly stimulates rat VSMC proliferation and activates MAPK in vitro. This might be one of the mechanisms underlying the progression of atherosclerotic lesions in end-stage renal disease patients.
H Yamamoto, and
S Tsuruoka, and
T Ioka, and
H Ando, and
C Ito, and
T Akimoto, and
A Fujimura, and
Y Asano, and
E Kusano
April 2011,
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy,
H Yamamoto, and
S Tsuruoka, and
T Ioka, and
H Ando, and
C Ito, and
T Akimoto, and
A Fujimura, and
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E Kusano
January 1997,
Experimental and molecular pathology,
H Yamamoto, and
S Tsuruoka, and
T Ioka, and
H Ando, and
C Ito, and
T Akimoto, and
A Fujimura, and
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August 2014,
Endocrine,
H Yamamoto, and
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T Ioka, and
H Ando, and
C Ito, and
T Akimoto, and
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January 2009,
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation,
H Yamamoto, and
S Tsuruoka, and
T Ioka, and
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T Akimoto, and
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January 1999,
Transplantation proceedings,
H Yamamoto, and
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January 2014,
PloS one,
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December 2020,
Atherosclerosis,
H Yamamoto, and
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C Ito, and
T Akimoto, and
A Fujimura, and
Y Asano, and
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January 2020,
International journal of medical sciences,
H Yamamoto, and
S Tsuruoka, and
T Ioka, and
H Ando, and
C Ito, and
T Akimoto, and
A Fujimura, and
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January 2023,
Journal of vascular research,
H Yamamoto, and
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T Ioka, and
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C Ito, and
T Akimoto, and
A Fujimura, and
Y Asano, and
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July 2022,
Clinical and experimental nephrology,
