Indoxyl sulfate stimulates monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells by inducing oxidative stress through activation of the NADPH oxidase-nuclear factor-κB pathway.

BACKGROUND: Chronic kidney disease (CKD) is recognized as a common condition that elevates the risk of atherosclerotic cardiovascular disease (CVD). Evidence suggests that increased oxidative stress is an emerging key mechanism of atherosclerosis in CKD. One recent study reported that indoxyl sulfate (IS), a uremic toxin derived from dietary protein, could cause vascular disorder, however, little is known about the mechanism involved. The present study examined the signaling pathway that is activated by IS to induce monocyte chemoattractant protein-1 (MCP-1), which plays an important role in the development of atherosclerosis, in cultured human umbilical vein endothelial cells (HUVEC). METHODS AND RESULTS: We show that IS enhanced reactive oxygen species (ROS) production, assessed by dihydroethidium staining, by HUVEC. IS also induced the expression of MCP-1, which was measured by enzyme-linked immunosorbent assay and real-time reverse transcription-polymerase chain reaction. These changes were suppressed by apocynin, a specific inhibitor of NADPH oxidase. Furthermore, IS induced the expression of NADPH oxidase 4 (Nox4) mRNA. IS-induced stimulation of ERK1/2 and p38 phosphorylation, detected by immunoblotting, was inhibited by apocynin. Finally, IS activated NF-κB, which was suppressed by inhibiting ERK1/2 and p38, resulting in reduced MCP-1 expression. These results suggest that IS increases NADPH oxidase-derived ROS, which in turn, activates the MAPK/NF-κB pathway and leads to induction of MCP-1 expression in HUVEC. CONCLUSIONS: These findings raise the possibility that IS plays an important pathophysiological role in the development of CVD in individuals with CKD.

Thyroid storm associated with Graves' disease covered by diabetic ketoacidosis: A case report.

BACKGROUND: Thyroid storm is a condition in which multiple organ dysfunction results from failure of the compensatory mechanisms of the body owing to excessive thyroid hormone activity induced by some factors in patients with thyrotoxicosis. While diabetic ketoacidosis (DKA) is an important trigger for thyroid storm, simultaneous development of DKA and thyroid storm is rare. CASE PRESENTATION: A 59-year-old woman with no history of either diabetes mellitus or thyroid disease presented to our hospital because of developing nausea, vomiting and diarrhea for 2 days. Physical examination showed mild disturbance of consciousness, fever, and tachycardia. There were no other signs of thyrotoxicosis. Laboratory studies revealed elevation of random blood glucose and glycosylated hemoglobin, strongly positive of urine acetone, and metabolic acidosis. Since DKA was diagnosed, we initiated the patient on treatment with administration of insulin and adequate fluid replacement. Although the hyperglycemia and acidosis were immediately relieved, the disturbance of consciousness and tachycardia remained persistent. Levels of FT3 and FT4 were extremely high and TSH was below the detectable limit. TRAb was positive. The thyroid storm score of Burch & Wartofsky was 75/140, and the thyroid storm diagnostic criteria of the Japan Thyroid Association were satisfied. Oral administration of thiamazole, potassium iodide and propranolol resulted in immediate relief of the tachycardia. DISCUSSION: We encountered a case of thyroid storm associated with Graves' disease covered by DKA. Thyroid storm and DKA are both potentially fatal, and the prognosis varies depending on whether or not these conditions are detected and treated sufficiently early. The thyroid storm diagnostic criteria prepared in 2008 by the Japan Thyroid Association are very simple as compared to the Burch & Wartofsky scoring system for thyroid storm. The Japanese criteria may be useful in the diagnosis of this condition since they enable clinicians to identify a broad range of cases with thyroid storm. When dealing with cases of DKA or thyroid storm, it seems essential to bear in mind the possibility of the coexistence of these two diseases.