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1 Department of Medicine, Nephrology Division, Medical University of South Caroliina, Charleston, SC, USA; Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC, USA
* To whom correspondence should be addressed. E-mail: gelascoa{at}musc.edu.
Indoxyl sulfate is a protein metabolite that is concentrated in the serum of patients with chronic renal insufficiency. It is also a uremic toxin that has been implicated in the progression of chronic renal disease in rodent models. We have previously shown 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 µM, 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 = 550 µM) by using the ROS sensitive fluorescent dye CM-DCF. ROS generation was only partially ([[dsim]]50%) inhibited by the NADPH oxidase inhibitor, diphenylene iodinium, at low (
300 µM) 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 O2.- production; and intracellular hydroxyl radical production that may derive from an initial O2.- burst. These results document that indoxyl sulfate, when applied to renal mesangial cells at pathological concentrations, induces rapid and complex changes in mesangial cell redox.
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