Hexavalent chromium intoxication induces intrinsic and extrinsic apoptosis in human renal cells.

Hexavalent chromium [Cr(VI)], is a well­known toxic form of the heavy metal chromium in the natural environment. Clinical evidence has indicated that exposure to Cr(VI) can cause severe renal damage. The production of reactive oxygen species (ROS) due to intracellular reduction of Cr(VI) is the main mechanism underlying the induction of cellular dysfunction and apoptosis. The present study aimed to investigate in detail the apoptotic pathways induced by Cr(VI)­exposure in a human immortalized proximal tubular epithelial cell line HK­2, in order to understand the mechanism involved therein. Exposure to 10 µM potassium dichromate (K2Cr2O7), a toxic compound of Cr(VI), significantly decreased cell viability after 24 and 48 h of incubation and induced intracellular ROS generation. The expression levels of markers that activate the apoptotic pathway including cleaved caspase­3 and poly (ADP­ribose) polymerase were significantly upregulated in K2Cr2O7­exposed HK­2 cells. In addition, the induction of intrinsic and extrinsic apoptotic markers was detected in K2Cr2O7­exposed HK­2 cells. In summary, the present study described for the first time the novel apoptotic mechanism of Cr(VI)­toxicity in human renal cells which may be beneficial in designing optimal clinical treatment for renal damage caused by acute Cr(VI) toxicity.

Optimal Regimen of N-Acetylcysteine on Chromium-Induced Renal Cell Damage.

Chromium (Cr) is a well-known heavy metal that can cause renal damage. The production of reactive oxygen species (ROS) due to chromium-induced toxicity induces cell dysfunction, apoptosis, and death. N-acetylcysteine (NAC) is an antioxidant used as an antidote for chromium-induced toxicity. However, the optimal regimen and protective mechanisms of NAC are not fully understood in human renal cells. Our results showed that exposure to 10 µM K2Cr2O7, a toxic Cr(VI) compound, induced apoptosis and production of intracellular ROS in the human proximal tubular epithelial cell line HK-2. Supplements of 600 or 1000 µg/mL NAC inhibited intracellular ROS in HK-2 cells exposed to Cr(VI) and significantly increased cell viability within 2 h of Cr(VI)-induced cytotoxicity. Moreover, Cr(VI) induced the expression of apoptosis markers, including cleaved-caspase-3, cleaved-poly (ADP-ribose) polymerase, cleaved-caspase 8, and cleaved-caspase 9, and altered the expression ratio of Bax/Bcl-xL. Expression of apoptosis markers within 2 h of Cr(VI)-induced cytotoxicity in cells treated with 600 µg/mL NAC was significantly suppressed. However, delayed treatment with NAC at 4 h and 8 h after exposure to Cr did not suppress the activation of apoptotic pathways. In summary, our study reports the optimum timing and dose of NAC for the protection of human renal proximal tubular cells from Cr(VI)-induced cell death. The NAC treatment strategy described could be applied in clinical practice to suppress renal cell apoptosis, which in turn could rescue renal function.

A survival case of intravenous paraquat intoxication: A case report.

RATIONALE: Paraquat, an agent highly toxic to humans and animals, is a widely used herbicide and also commonly used for suicide attempts in Taiwan. The most common route of intoxication is oral ingestion, and parenteral poisoning is respectively rare. PATIENT CONCERNS: A 39-year-old illicit abuser of heroin and amphetamine injected 0.5 mL of 24% paraquat directly into his right cephalic vein due to hallucination. The patient was brought to our emergency department for management 4 hours after injection. He was fully conscious and had normal vital signs. Systemic review showed mild dyspnea, abdominal pain and right wrist pain over the injection site. The only abnormal physical finding was erythema over the injection site and epigastric tenderness. DIAGNOSIS: Laboratory investigations, including complete blood count, liver and renal function, and electrolytes initially yielded normal results. Urinalysis showed normal findings except a positive urine paraquat test (4+). The initial plasma paraquat concentration was 0.51 µg/mL. INTERVENTIONS: He was admitted to the intensive care unit and underwent one session of charcoal hemoperfusion therapy. Acute kidney injury developed on the fourth day after intoxication, with the level of serum creatinine rising rapidly from 0.96 to 4.57 mg/dL and the daily urine output decreased noticeably from > 2000 to 900 mL. The serum creatinine level improved gradually with adequate fluid supplementation. OUTCOMES: The patient was discharged 13 days later in a stable condition. LESSONS: Intravenous paraquat intoxication is rare. Patients who suffer from intravenous intoxication may not directly suffer from mucosal irritation, but the clinical onset of systemic effects is more immediate and lethal. The prognosis of paraquat poisoning is determined by the time of poisoning and the plasma paraquat concentration before treatment. Proudfoot's curve provides a simple method of predicting the survival rate. The most effective mode of management is extracorporeal therapy, and immunosuppressive or antioxidant therapies have shown insufficient evidence of benefit.