Effects of pyrrolidine dithiocarbamate on high-fat diet-induced metabolic and renal alterations in rats

Abstract

Aims: We investigated the effects of the nuclear factor kappa B (NFκB) blocker pyrrolidine dithiocarbamate (PDTC) on high-fat diet (HFD)-induced metabolic and renal alterations in obese and lean Zucker rats (OZR and LZR, respectively).Main methods: Rats were fed a HFD resembling the typical "Western" diet or a regular diet (RD) and allowed free access to tap water or tap water containing PDTC (150 mg/kg body weight) for 10 weeks; rats were then sacrificed. Total ROS production rates were measured using electron paramagnetic resonance spectroscopy, and superoxide production was measured with lucigenin assay. Blood, plasma, and urine were analyzed. Semi-quantitative reverse transcriptase-polymerase chain reaction and electrophoretic mobility shift assay were conducted to assess NFκB mRNA levels and DNA binding activities, respectively; immunofluorescence was performed to assess protein levels.Key findings: OZR-HFD rats exhibited significantly higher levels of total renal cortical reactive oxygen species production, plasma lipids, insulin, C-reactive protein, blood urea nitrogen, creatinine, and urinary albumin excretion than all other groups (p<0.05); these changes were accompanied by a significant decrease in plasma high density lipoprotein levels (p<0.05). Gene expression levels of desmin, cytokine and oxidative stress genes were significantly higher in the renal cortical tissues of OZR-HFD; NFκB p65 DNA binding activity was also significantly higher in these animals. PDTC attenuated these changes.Significance: Our data suggest that NFκB blockade may prove beneficial in treating the nephropathy often associated with metabolic syndrome.

Pyrrolidine dithiocarbamate enhances hepatic glycogen synthesis and reduces FoxO1-mediated gene transcription in type 2 diabetic rats

“…These results are in part contradictory to those of Ebenezer et al (9), in which PDTC was found to lower total and VLDL cholesterol, whereas it raised HDL cholesterol in rats fed a HFD. In the Ebenezer et al (9) study, homozygous Zucker fatty (fa/fa) and heterozygous (fa/ϩ) rats were used, whereas Wistar rats were chosen for our study.…”

“…In the Ebenezer et al (9) study, homozygous Zucker fatty (fa/fa) and heterozygous (fa/ϩ) rats were used, whereas Wistar rats were chosen for our study. In addition, in the study of Ebenezer et al (9), rats were allowed free access to water containing PDTC (150 mg/kg) for a total of 10 wk. In contrast, our protocol called for ip administration of PDTC (50 mg·kg body wt Ϫ1 ·day Ϫ1 ) for 1 wk.…”

“…PDTC is widely used as an inhibitor of the transcription factor nuclear factor-B (NF-B) in cellular and animal models of inflammation (30,32). Various studies have demonstrated that PDTC can counteract the toxic effects of free radicals and interfere with the generation of proinflammatory cytokines (9,21). There is an accumulating body of evidence showing that PDTC has beneficial effects on several vascular diseases (19,25) and that it lowers blood glucose levels in diabetic rats significantly (38) through mechanisms that have not been fully elucidated.…”

Impact of Pyrrolidine Dithiocarbamate and Interleukin-6 on Mammalian Target of Rapamycin Complex 1 Regulation and Global Protein Translation

“…It has been suggested that PDTC prevents dyslipidemia and renal lesions in rats fed a high-fat diet, most likely because of attenuation of proinflammatory gene expression and improvement of metabolic parameters (Ebenezer et al, 2009). Glucosestimulated insulin secretion in human islets exposed to high glucose is restored after exposure to PDTC (Maedler et al, 2002).…”

“…Furthermore, PDTC provides neuroprotection in hypoxic-ischemic injury and against liver injury during intestinal ischemia and reperfusion in rats (Nurmi et al, 2006;Tian et al, 2006). Although some studies have suggested that PDTC significantly reduces inflammatory processes through the inhibition of the transcription factor nuclear factor-B (Schreck et al, 1992;Cuzzocrea et al, 2002;Ebenezer et al, 2009), this has not been observed in all studies (Malm et al, 2007;Huang et al, 2008). In fact, PDTC confers adaptive protection of stressed cells from proinflammatory conditions through activation of the metal-activated transcription factor heat shock factor 1 (HSF1) (Song et al, 2010).…”