Indoxyl sulfate induces complex redox alterations in mesangial cells

Abstract

Indoxyl sulfate is a protein metabolite that is concentrated in the serum of patients with chronic renal insufficiency. It also is a uremic toxin that has been implicated in the progression of chronic renal disease in rodent models. We have shown previously that mesangial cell redox status is related to activation of mitogen-activated protein kinases and cell proliferation, which are factors related to glomerular damage. We used three methods to examine the ability of indoxyl sulfate to alter mesangial cell redox as a possible mechanism for its toxicity. Indoxyl sulfate increases mesangial cell reduction rate in a concentration-dependent manner as demonstrated by redox microphysiometry. Alterations occurred at concentrations as low as 100 M, with more marked alterations occurring at higher concentrations associated with human renal failure. We demonstrated that indoxyl sulfate induces the production of intracellular reactive oxygen species (ROS) in mesangial cells (EC50 ϭ 550 M) by using the ROS-sensitive fluorescent dye CM-DCF. ROS generation was only partially (ϳ50%) inhibited by the NADPH oxidase inhibitor diphenylene iodinium at low (Յ300 M) indoxyl sulfate concentrations. Diphenylene iodinium was without effect at higher concentrations of indoxyl sulfate. We also used electron paramagnetic spin resonance spectroscopy with extracellular and intracellular spin traps to show that indoxyl sulfate increases extracellular SOD-sensitive O 2

An Oral Adsorbent, AST-120 Protects Against the Progression of Oxidative Stress by Reducing the Accumulation of Indoxyl Sulfate in the Systemic Circulation in Renal Failure

“…Previous studies of the induction of ROS by IS were limited to the use of renal tubule cells (OK cells) and mesanginal cells, but no findings in intravascular cell lines have been reported (10,14). However, our results clearly show that IS also induce ROS production in HUVECs to a remarkably extent and this was largely inhibited by AST-120 pretreatment.…”

“…We previously reported that IS was taken up by proximal tubular cells by organic anion transporters (Oat1, Oat3) and Motojima et al demonstrated that such cellular uptake causes proximal tubular injury (28,29). In addition, Gelasco et al found that IS stimulates the production of intracellular and extracellular ROS in rat mesanginal cells, through a pathway that most likely involves NADPH oxidase or NADPH like oxidase (14). However, determining the molecular mechanism by which IS induces the ROS production in the endothelial cells will require further in vitro studies, which are now underway in our laboratory.…”

“…The toxin is thought to be involved in the progression of CRF because it is present in high levels in the serum of patients with CRF and causes tubulointerstitial injuries in rodent models (12,13). Several researchers have recently reported that IS has the potential to produce oxidative stress in renal proximal tubular cells and mesangial cells (10,14). Moreover, supplementation of excessive dietary tryptophan, a precursor of IS, was reported to enhance plasma lipid peroxidation in rats (15).…”

AST-120 Treatment in Pre-Dialysis Period Affects the Prognosis in Patients on Hemodialysis

“…Also, other groups reported that indoxyl sulfate promoted oxidative stress in endothelial cells and the kidney. [16][17][18][19] These results strongly suggest the involvement of uremic toxins in the development of atherosclerosis. AST-120 has been known to decrease serum levels of indoxyl sulfate significantly in CKD rat models and also in CKD patients.…”

Síndrome de la bolsa de orina púrpura: un fenómeno inusual y muy llamativo

“…La coloración púrpura puede aparecer desde horas hasta días posteriores a la colocación del catéter urinario y se hace más intensa a medida que pasa el tiempo, sin realizar un recambio oportuno de la bolsa colectora de orina. Es interesante observar que la orina no es púrpura al ser colocada en otro recipiente estéril 9 .…”